maladies du sang, Lille, France,
15
Istituto Nazionale Tumori Regina
Elena di Roma, Ematologia, Roma, Italy,
16
University of Torino, A.O.U.
"Città della Salute e della Scienza di Torino", Division of Hematology,
Department of Molecular Biotechnologies and Health Sciences, Torino,
Italy,
17
Azienda sanitaria locale Biella, Ospedale degli Infermi Ema-
tologia, Biella, Italy,
18
CHU de Nantes Hôtel Dieu, Service d'héma-
tologie clinique, Nantes, France,
19
CLCC Henri Becquerel, Service
d'Hématologie, ROUEN, France,
20
Azienda Ospedaliera Nazionale SS.
Antonio e Biagio e C. Arrigo, SC Ematologia, Alessandria, Italy,
21
Ospedale Oncologico, Struttura complessa di Ematologia e CTMO,
Cagliari, Italy,
22
Azienda USL Toscana nord ovest, Ospedali Riuniti
Livorno Ematologia, Livorno, Italy,
23
Presidio Ospedaliero “Andrea
Tortora” di Pagani, Ematologia, Pagani, Italy,
24
Ospedale Infermi di
Rimini, Ematologia, Rimini, Italy,
25
Università La Sapienza Policlinico
Umberto I, Dipartimento di Medicina Traslazionale e di Precisione,
Roma, Italy,
26
Lymphoma Unit, Oncology and Hematology, Pescara,
Italy,
27
CHU Montpellier, Hématologie clinique, Montpellier, France,
28
CHU Dijon Bourgogne, Hematologie Clinique, Dijon, France,
29
Fon-
dazione IRCCS Istituto Nazionale dei Tumori, S.C. Ematologia, Milano,
Italy,
30
HenriMondor University Hospital, APHP, Lymphoid Malig-
nancies Unit, Crétiel, France,
31
CHU de Rennes, Hématologie clinique,
Rennes, France,
32
Azienda Ospedaliera Santa Maria Terni, SCU
Oncoematologia, Terni, Italy,
33
Azienda USL Toscana sud est, Emato-
logia Ospedale San Donato, Arezzo, Italy,
34
ASST Sette Laghi, Ospe-
dale di Circolo e Fondazione Macchi Ematologia, Varese, Italy,
35
IRCCS CROB, Ematologia, Rionero in Vulture, Italy,
36
Azienda
Ospedaliero Universitaria di Parma, Ematologia e Centro trapianti
midollo osseo, Parma, Italy,
37
Centro Riferimento Oncologico, Divisione
di Oncologia Medica A, Aviano, Italy,
38
Foundation for the Institute of
Oncology Research (IOR), International Extranodal Lymphoma Study
Group, Bellinzona, Switzerland,
39
Università della Svizzera Italiana,
Institute of Oncology Research, Bellinzona, Switzerland,
40
Foundation
for the Institute of Oncology Research (IOR), International Extranodal
Lymphoma Study Group, Oncology Institute of Southern Switzerland,
Medical Oncology Clinic, Bellinzona, Switzerland,
41
Oncology Institute
of Southern Switzerland, Medical Oncology Clinic, Bellinzona,
Switzerland,
42
APHP Hôpital SaintLouis, Service d'Hématologie
Oncologie, Paris, France
Introduction: The International Extranodal Lymphoma Study Group
(IELSG), in collaboration with the Italian Lymphoma Foundation (FIL)
and the Lymphoma Study Association (LYSA), conducted the IELSG38
trial to evaluate the role of rituximab maintenance in mucosa asso-
ciated lymphoid tissue (MALT) lymphoma patients (pts) after the
administration of a frontline rituximabchlorambucil regimen. In a
prior study (IELSG19), this regimen, without maintenance, produced
superior eventfree (EFS) and progressionfree survival (PFS) in
comparison to either agent alone.
Methods: Pts with MALT lymphoma arisen at any extranodal site, de
novo, or relapsed following local therapy and/or antibiotics were
eligible.
Treatment consisted of an induction phase with chlorambucil (6 mg/
m2/d orally on weeks 1 to 6, 9 to 10, 13 to 14, 17 to 18, and 21 to 22)
and rituximab (375 mg/m2 intravenously on day 1 of week 1, 2, 3, 4
and 1400 mg subcutaneously on week 9, 13, 17, and 21). Pts with
complete (CR), partial response (PR) or stable disease were eligible
for maintenance with subcutaneous rituximab 1400 mg every two
months for two years.
Results: The study completed its planned accrual enrolling 112 pa-
tients, 53 women and 59 men (median age 65 years; range 3286).
Primary lymphoma localization was gastric in 32% and nongastric in
68% of pts. Over half of pts (56%) had advanced disease (stage IIIIV).
MALT IPI showed low risk in 29%, intermediate risk in 40% and high
risk in 30%.
Twentyfour pts did not complete study treatment. Fifteen ceased
before maintenance: 4 due to drug related (DR) adverse events
(AEs), 3 to nonDR AEs, 2 to high grade transformation, 1 each for
progressive disease (PD), second tumor, protocol deviation, inves-
tigator decision, patient decision, consent withdrawal. Nine dis-
continued during maintenance (3 DR AEs, 2 PD, 2 second tumors,
1 patient decision, 1 protocol deviation). The most common AEs of
grade3 were hematologic (neutropenia in 33%, lymphocytopenia
in 16%, leukopenia in 14%). Five pts experienced DR serious AEs
(fever of unknown origin, sepsis, pneumonia, acute respiratory
distress syndrome and progressive multifocal leukoencephalop-
athy). Best response was CR in 87% of pts. In the intentionto
treat population, CR rate increased over time from 53% at the
end of induction to 65% at the end of maintenance. With a median
followup of 65 months (IQR, 5869), median EFS, PFS and OS
were not reached. The 5year EFS, PFS and OS were respectively
76% (95%CI, 6783%), 87% (95%CI, 7992%) and 93% (95%CI, 86
96%).
Conclusions: IELSG38 is the first trial that specifically evaluated
subcutaneous rituximab maintenance in patients with MALT
lymphoma. No new safety signals were identified. Longterm dis-
ease control was achieved in the majority of patients and,
despite the inclusion of more high risk patients (30% vs. 17%), the
5 year PFS (87% vs. 72%) compared favorably with the IELSG19
trial.
132
-
SUPPLEMENT ABSTRACTS
The research was funded by: F. HoffmannLa Roche Ltd, Basel pro-
vided the drug rituximab free of charge and partially supported the
study financially.
Keywords: Chemotherapy Combination, Therapies Immunotherapy
Conflicts of interests pertinent to the abstract
P. Feugier
Consultant or advisory role: Roche
Educational grants: Roche
F. Merli
Consultant or advisory role: Roche
Educational grants: Roche
E. Gyan
Consultant or advisory role: Roche
F. Morschhauser
Consultant or advisory role: Roche
A. Pulsoni
Consultant or advisory role: Roche, Merck, Pfizer, Sandoz, Takeda,
Gylead, Bristol Myers Squibb
G. Cartron
Consultant or advisory role: Roche, CelgeneBMS
Honoraria: Sanofi, Celgene, Gilead, Novartis, Roche, Abbvie
O. Casasnovas
Consultant or advisory role: Roche, Takeda, MSD, BMS, Gilead
Honoraria: Roche, Takeda, MSD, BMS, Gilead
Research funding: Roche, Gilead
Educational grants: Roche, Amgen
C. Haioun
Consultant or advisory role: Roche
Honoraria: Roche
A. M. Liberati
Consultant or advisory role: Servier
Research funding: Novartis, Janssen, Abbvie, Roche, Amgen, Celgene,
BMS, Takeda, Incyte, Beigene, Oncopeptides AB, Verastem, Kar-
yopharm, Archigen, Debiopharm International, Morphosys, Fibrogen,
Onconova Therapeutics Inc
D. Rossi
Honoraria: Abbvie, Astra Zeneca, Janssen
Research funding: Abbvie, Astra Zeneca, Janssen
S. Luminari
Consultant or advisory role: Rochem, Janssen, BMS, Regeneron,
Genmab, Incyte
Educational grants: Janssen, BMS
A. Stathis
Consultant or advisory role: Roche, Bayer, Eli LIlly
Research funding: Merck, Bayer, Roche, Novartis, Pfizer, ADC The-
arapeutics, MEW Pharma, Eli Lilly
C. Thieblemont
Consultant or advisory role: Roche, Incyte, Janssen, Gilead, Kyte,
Novartis
080 |RESPONSE ADAPTED POST INDUCTION THERAPY
IN FOLLICULAR LYMPHOMA: UPDATED RESULTS OF
THE FOLL12 TRIAL BY THE FONDAZIONE ITALIANA LINFOMI
(FIL)
S. Luminari
1
, S. Galimberti
2
, A. Versari
3
, A. Tucci
4
, C. Boccomini
5
,
L. Farina
6
, F. Zaja
7
, L. Marcheselli
8
, S. Ferrero
9
, L. Arcaini
10
,
A. Pulsoni
11
, G. Musuraca
12
, C. Califano
13
, M. Merli
14
, A. Bari
15
,
A. Conconi
16
, I. del Giudice
17
, F. Re
18
, P. M. Stefani
19
, S. V. Usai
20
,
T. Perrone
21
, G. Gini
22
, B. Falini
23
, V. Gattei
24
, M. Manni
25
,
M. Ladetto
26
, D. Mannina
27
, M. Federico
25
1
Azienda Unità Sanitaria Locale IRCCS, Arcispedale Santa Maria
Nuova IRCCS, Hematology Unit and, University of Modena and Reggio
Emilia, Surgical, Medical and Dental Department of Morphological
Sciences related to Transplant, Oncology and Regenerative Medicine,
Reggio Emilia, Italy,
2
University of Pisa, Department of Clinical and
Experimental Medicine, Pisa, Italy,
3
Azienda Unità Sanitaria Locale
IRCCS Arcispedale Santa Maria Nuova, Medicina Nucleare, Reggio
Emilia, Italy,
4
ASST Spedali Civili di Brescia, SC Ematologia, Brescia,
Italy,
5
A.O.U. Città della Salute e della Scienza di Torino, SC Emato-
logia, Torino, Italy,
6
Fondazione IRCCS Istituto Nazionale dei Tumori di
Milano, Division of Hematology, Milano, Italy,
7
Università degli Studi
di Trieste, Dipartimento Clinico di Scienze mediche, chirurgiche e della
salute and, Azienda Sanitaria Universitaria Giuliano Isontina, SC
Ematologia, Trieste, Italy,
8
Fondazione Italiana Linfomi Onlus, FIL,
Modena, Italy,
9
University of Torino, Hematology, Department of
Molecular Biotechnologies and Health Sciences and, AOU “Città della
Salute e della Scienza di Torino”, Hematology 1, Torino, Italy,
10
Fon-
dazione IRCCS Policlinico San Matteo di Pavia, Division of Hematology
and, University of Pavia, Department of Molecular Medicine, Pavia,
Italy,
11
Sapienza Università di Roma, Dipartimento di Biotecnologie
Cellulari ed Ematologia, Roma, Italy,
12
IRCCS Istituto Romagnolo per
lo Studio dei Tumori (IRST) "Dino Amadori", Department of Hema-
tology, Meldola, Italy,
13
Ospedale Umberto I, U.O. Medicina
Oncoematologia, Nocera Inferiore, Italy,
14
University Hospital Ospedale
di Circolo e Fondazione Macchi, ASST Settelaghi, Varese, Italy,
15
Università di Modena e Reggio Emilia, Dipartimento di Scienze
Mediche e Chirurgiche MaternoInfantili e dell'Adulto, Modena, Italy,
16
Ospedale degli Infermi, Unit of Hematology, Biella, Italy,
17
Policlinico
Umberto I Università "La Sapienza" Istituto Ematologia, Diparti-
mento di Medicina Traslazionale e di Precisione, Roma, Italy,
18
Azienda Ospedaliero Universitaria di Parma, UO Ematologia e
CTMO, Parma, Italy,
19
General Hospital Ca' Foncello, Hematology,
Treviso, Italy,
20
Ospedale Oncologico Armando Businco, Division of
Hematology, Cagliari, Italy,
21
University of Bari, Hematology, Bari,
Italy,
22
Marche Polytechnic University, Department of Clinical and
Molecular Sciences, Hematology, Ancona, Italy,
23
Ospedale S. Maria
della Misericordia, University of Perugia, Institute of Hematology and
SUPPLEMENT ABSTRACTS
-
133
CREO (Center for HematoOncological Research), Perugia, Italy
24
Cen-
tro di Riferimento Oncologico di Aviano (CRO) IRCCS, Clinical and
Experimental OncoHematology Unit, Aviano, Italy,
25
University of
Modena and Reggio Emilia, Surgical, Medical and Dental Department
of Morphological Sciences related to Transplant, Oncology and
Regenerative Medicine, Modena, Italy,
26
Università del Piemonte Ori-
entale, Dipartimento di Medicina Traslazionale and, AO SS Antonio e
Biagio e Cesare Arrigo, SC Ematologia, Alessandria, Italy,
27
Azienda
Ospedaliera Papardo, UOC di Ematologia, Messina, Italy
Background: Two years of rituximab maintenance (RM) after first
line rituximabbased chemotherapy significantly improved
progressionfree survival (PFS) in patients with follicular lymphoma
(FL). However, one important question is whether this approach is
really suitable for all patients. Here, we report the results from the
FOLL12 study, comparing RM with a response adapted post
induction approach.
Methods: We randomly assigned treatment naïve, advanced stage,
high tumor burden FL patients to receive standard RM or a
responseoriented postinduction approach based on metabolic
response and molecular assessment of minimal residual disease
(MRD). End of Induction (EOI) metabolic response was centrally
defined applying the 5point Deauville scale (DS) that defined
Complete metabolic response (CMR) in case for DS 13. MRD was
defined according to nested PCR assessment of Bcl2/IgH rear-
rangement on bone marrow and peripheral blood and was evalu-
ated only for patients with a molecular marker (MM) at baseline
assessment. Post induction therapy in the experimental arm con-
sisted of: CMR and MRDpatients, observation; CMR and MRD+
(EOI or Follow up) 4 weekly rituximab until MRDfor up to 3
courses; no CMR, one dose of ibritumomab tiuxetan followed by
standard RM. The primary endpoint was 3year Progression Free
Survival (PFS).
Results: This analysis was conducted on 712 out of 807 randomized
patients who achieved at least a Partial response at EOI. After a
median followup of 53 months (range 1 to 92), patients in the
standard arm had a significantly better PFS than the experimental
approach (3year PFS 86% vs 72%, P <0.001). The improved PFS of
FIGURE 1 Progression free survival by study arm for patients’ sugroups: A) Patients with complete metabolic response (CMR) after
induction therapy; B) Patients with both CMR and complete molecular response (MRD); C) patients with CMR and MRD+; D) Patients
without CMR Legend to figure: A: reference arm; B: experimental arm
134
-
SUPPLEMENT ABSTRACTS
the standard vs experimental arm was confirmed in the study sub-
groups (Figure 1); CMR patients (A) (N =628: 3yr PFS 90% and 72%
for standard and experimental arm, respectively (P = < 0.001); CMR
and MRD(B) (N =299: 92% vs 78%; P <0.001); CMR and MRD+
(C) (N =46: 96% and 45%; p =0.004). In the group of 65 patients
without CMR no difference in PFS was observed between reference
and experimental arm (P =0.274) (D).
At time of last update 30 deaths were reported, of which 15 were
associated with disease progression or recurrence. The 3yr OS was
98% (95%CI 9699) and 97% (95%CI 9599) in the reference and
experimental arm, respectively (p =0.238).
Conclusions: A metabolic and a molecular response adapted
therapy as assessed in the FOLL12 study was associated with a
significantly inferior PFS compared to 2year rituximab mainte-
nance. The better efficacy of standard RM was confirmed in the
subgroup analysis and in particular for patients achieving both
CMR and MRD.
The research was funded by:
Società Italiana di Ematologia (SIE)
Associazione Angela Serra per la Ricerca sul Cancro
Ministero della Salute, Direzione Generale della ricerca e dell’In-
novazione in sanità (BANDO PROGETTI DI RICERCA GIOVANI
RICERCATORI RICERCA FINALIZZATA 20112012)
Keywords: Indolent nonHodgkin, lymphoma Combination
Therapies
No conflicts of interests pertinent to the abstract.
081 |IMMUNE PRIMING WITH NIVOLUMAB FOLLOWED BY
NIVOLUMAB & RITUXIMAB IN 1
ST
LINE TREATMENT OF
FOLLICULAR LYMPHOMA: THE PHASE 2 1
ST
FLOR STUDY
E. A. Hawkes
1
, S. T. Lee
2
, G. Chong
3
, M. Gilbertson
4
, A. Grigg
5
,
L. Churilov
6
, T. Fancourt
7
, C. Keane
8
, D. Ritchie
9
, R. Koldej
10
,
R. Agarwal
11
, K. Manos
12
, C. Smith
13
, K. Houdyk
13
, J. Hawking
13
,
A. Barraclough
14
1
Olivia NewtonJohn Cancer Research and Wellness Centre, Medical
Oncology and Haematology, Melbourne, Australia,
2
Austin Health,
Molecular Imaging and Therapy, Melbourne, Australia,
3
Ballarat
Regional Intergrated Cancer Centre, Haematology and Oncology, Bal-
larat, Australia,
4
Monash Health, Haematology, Melbourne, Australia,
5
Austin Health, Haematology, Melbourne, Australia,
6
Melbourne Brain
Centre, Florey Institute of Neuroscience and Mental Health, Melbourne,
Australia,
7
Austin Health, Anatomical Pathology, Melbourne, Australia,
8
Princess Alexandra Hospital, Haematology, Brisbane, Australia,
9
Peter
MacCallum Cancer Centre and Royal Melbourne Hospital, Haematology,
Melbourne, Australia,
10
The Royal Melbourne Hospital, ACRF Trans-
lational Research Laboratory, Melbourne, Australia,
11
Austin Health,
Molecular Diagnostics, Melbourne, Australia,
12
Austin Health, Haema-
tology, Melbourne, Australia,
13
Austin Health, Cancer Clinical Trials
Centre, Melbourne, Australia,
14
Fiona Stanley Hospital, Haematology,
Perth, Australia
Introduction: Standard of care immunochemotherapy in frontline
(1L) follicular lymphoma (FL) is highly efficacious but not without
significant toxicity. High rates of grade 35 adverse events (AEs),
primarily infection and bone marrow suppression, are experienced in
up to 75% of patients. A more tolerable but equally effective
approach is required. PD1 inhibition, in combination with rituximab
(R), increases T cell antitumour effect & enhances NK cell antibody
dependent cell cytotoxicity, with proven efficacy in relapsed FL. The
concept of ‘priming’ the immune system with nivolumab (N) prior to
tumourdirected therapy has rationale and evidence, but the safety
of this approach in 1L FL is not described.
Methods: ‘1
st
FLOR’ (NCT03245021) is an openlabel, multicentre,
phase 2, Simon's 2stage study of N +R (N =39). Key eligibility were
stage IIIIV grade 13A FL requiring 1L systemic therapy; ECOG 2;
adequate organ function. All patients (pts) receive induction N
240mg IV 2weekly for 4 cycles. Pts with complete response (CR)
receive 4 further cycles of 240mg IV N monotherapy then 12 cycles
of maintenance N 480mg IV 4weekly. Pts with 2 IV R 2weekly for 4
cycles followed by maintenance N+R (N 480mg 4 weekly for 12
cycles; R 12 weekly for 8 cycles). Primary endpoint (EP) was G3
toxicity rate. Secondary EPs were response rate, overall toxicity,
progression free survival (PFS) & overall survival (OS).
Results: Between September 2017 to March 2020, 39 pts were
enrolled. Baseline characteristics included median age of 54 (range:
2879), stage IV disease in 67%, B Symptoms & bulk (7cm) in 23%
each, intermediatehigh risk FLIPI in 74%.
The primary EP was met, with 16 pts (41%) having G3 toxicity at
end of induction. Nonimmune AEs were predominantly G12; most
commonly infection (67%) & fatigue (64%). G34 Immunerelated AEs
were infrequent and included pancreatitis plus hepatitis (N =1),
pancreatitis alone (N =1), rash (N =1), transaminitis (N =2),
hypocortisolism (N =1), hyperglycaemia (N =3) and asymptomatic
lipase/amylase increase (N =3).
Median followup was 17.5 months (range: 739). Overall response
rate was 92% (36/39) with CR in 54% (21/39). Median time to CR
was 5 months (m) (range: 225). Nine pts (23%) discontinued treat-
ment; 7 due to progressive disease (1 pt died of transformed FL), 2
developed constitutional symptoms (1 stable disease, 1 partial
response). In 25 evaluable pts, 12m PFS & OS is 72% (CI 5188) &
96% (CI 80100).
Biomarker analysis is in progress.
Conclusion: Immunepriming with singleagent N, then combination
N+R in 1L FL is associated with favourable toxicity and high
ORR & CR rates potentially providing an alternative to
chemotherapy.
Acknowledgements
Bristolmyers Squibb provided funding and nivolumab for this study.
EA previously submitted to ASCO 2021.
The research was funded by: Bristolmyers Squibb
SUPPLEMENT ABSTRACTS
-
135
Keywords: Immunotherapy, Indolent nonHodgkin lymphoma
Conflicts of interests pertinent to the abstract
E. A. Hawkes
Consultant or advisory role: Antigene, Janssen, Gilead, Merck Sharpe
and Dohme, Astra Zenica, Bristol Myers Squibb/Celgene, Roche
Honoraria: Roche, AstraZenica, Janssen
Research funding: Roche, Bristol Myers Squibb/Celgene, Merck KgA,
Astra Zenica,
Educational grants: Roche, Janssen
G. Chong
Consultant or advisory role: Bristol Myers Squibb
Research funding: Bristol Myers Squibb, Merck Serono, Hutchison
Medipharma, Regeneron, AstraZeneca, Pharmacyclics, Bayer, Servier,
Isofol
A. Grigg
Consultant or advisory role: Janssen, Sylvant
Honoraria: MSD, Gilead, Roche, Novartis
C. Keane
Consultant or advisory role: MSD, Celgene, Gilead Sciences, Roche,
Janssen
Honoraria: Gilead Sciences, Roche, Celgene, MDS oncology
Research funding: Bristol Myers Sqibb
Educational grants: Roche, MSD oncology, Celgene, Gilead Sciences
R. Koldej
Research funding: CRISPR Therapeutics
Educational grants: NanoString Technologies
K. Manos
Educational grants: BristolMyers Squibb
A. Barraclough
Educational grants: Roche
SESSION 13: CART CELL THERAPY
082 |CARHEMATOTOX: A DISCRIMINATIVE MODEL FOR CAR
TCELL RELATED HEMATOTOXICITY IN RELAPSED/REFRACTORY
LARGE BCELL LYMPHOMA
K. Rejeski
1
, A. Perez
2
, P. Sesques
3
, C. Berger
4
, L. Jentzsch
5
,
D. Mougiakakos
6
, L. Frölich
1
, J. Ackermann
1
, V. Bücklein
1
,
V. Blumenberg
1
, C. Schmidt
1
, L. Jallades
3
, B. Fehse
4
, C. Faul
5
,
P. Karschnia
7
, O. Weigert
1
, M. Dreyling
1
, E. Hoster
8
, F. Locke
2
,
M. von BergweltBaildon
1
, A. Mackensen
6
, W. Bethge
5
, F. Ayuk
4
,
E. Bachy
3
, G. Salles
9
, M. Jain
2
, M. Subklewe
1
1
University Hospital of the LMU Munich, Department of Hematology/
Oncology, Munich, Germany,
2
Moffitt Cancer Center, Department of
Blood and Marrow Transplant and Cellular Immunotherapy, Moffitt
Cancer Center, Tampa, USA, Tampa, USA,
3
Hospices Civils de Lyon,
Institut National de la Santé et de la Recherche Médicale (INSERM),
Lyon, France,
4
University Hospital HamburgEppendorf, Department of
Hematology, Oncology and Pulmonology, Hamburg, Germany,
5
Univer-
sity Hospital Tübingen, Department of Hematology, Oncology, Immu-
nology and Rheumatology, Tübingen, Germany,
6
University Hospital of
Erlangen, Department of Internal Medicine 5, Hematology and
Oncology, Erlangen, Germany,
7
University Hospital of the LMU Munich,
Department of Neurosurgery, Munich, Germany,
8
LMU Munich, Insti-
tute for Medical Informatics, Biometry and Epidemiology, Munich,
Germany,
9
MSKCC, Lymphoma Service, Department of Medicine, NYC,
New York, USA
Background: Hematotoxicity represents a frequent CAR Tcell
related adverse event that remains poorly understood. Prolonged
cytopenia and aplastic courses can predispose for severe infectious
complications, which represent the most common cause of non
relapse mortality after CAR Tcell therapy.
Methods: In this multicenter retrospective analysis, we studied
patterns of hematopoietic reconstitution and evaluated potential
predictive markers in 258 patients receiving Axicabtagene cil-
oleucel (Axicel, n =170) or Tisagenlecleucel (Tisacel, n =88)
for relapsed/refractory large Bcell lymphoma. Cytopenia was
graded according to CTCAE criteria with further sub
characterization of neutropenia as severe (ANC <500/µl), pro-
found (ANC <100/µl), protracted (7 days) and prolonged (ANC <
1000/µl after day 21). We studied the impact of baseline ( =prior
to lymphodepletion) clinical and laboratory markers on hematotox-
icity by uni& multivariate analysis using a binary logistic
regression analysis for the outcome of severe neutropenia 14
days ( =Test group) vs. <14 days ( =Control group). A discrim-
inative model termed CARHEMATOTOX was developed. Receiver
operator characteristic (ROC) analyses were used to assess mea-
sures of performance (sensitivity, specificity, AUC).
Results: Across all studied patients, we observed a high incidence
of profound and prolonged neutropenia of 72 and 64% respec-
tively (see Table). The incidence of severe neutropenia was 91%
with a median duration of 9 days (95% CI: 8 10 days). Uniand
multivariate analysis revealed an association between markers
associated with hematopoietic reserve (e.g. platelet count, ANC,
hemoglobin), baseline inflammatory state (e.g. ferritin, CRP), and
longer duration of neutropenia. In contrast, neither CRS/ICANS
grade nor peak cytokine levels were associated with long
neutropenia.
To develop the CARHEMATOTOX model in our training cohort (n
=58), the discriminatory threshold for each variable significantly
associated with hematotoxicity was determined on the basis of
optimizing the respective Youden J statistic. Additional weighting
of factors identified by stepwise multivariate analysis using a
backward elimination was applied. We validated the model in two
independent cohorts from Europe (n =91) and the USA (n =109)
and identified patients with severe neutropenia 14 days in both
(AUC =0.770.91, P <0.001, Sensitivity 84100%, Specificity 67
69%). A high CARHEMATOTOX score resulted in a longer
136
-
SUPPLEMENT ABSTRACTS
duration of neutropenia (12 vs. 5.5 days, P <0.001) and
discriminated for patients with aplastic features.
Conclusion: These findings underline the strikingly high incidence of
hematotoxicity after CAR Tcell therapy. The CARHEMATOTOX will
be useful for riskadapted management of hematotoxicity, to guide
prophylactic antimicrobial strategies, and to identify patients for
potential autologous stem cell backup.
Keywords: Risk Models, Cellular therapies, Aggressive Bcell non
Hodgkin lymphoma
No conflicts of interests pertinent to the abstract.
083 |EARLY PET RESPONSE PREDICTS OUTCOME IN LARGE B
CELL LYMPHOMA PATIENTS TREATED WITH CD19 CART
M. Cuadrado
1
, T. Menne
2
, G. Petrides
3
, W. Osborne
2
, V. Potter
1
,
R. Benjamin
1
, P. Patten
1
, D. Yallop
1
, R. Sanderson
1
, N. Mulholland
4
,
A. Kuhnl
1
1
King's College Hospital, Haematology, London, UK,
2
Freeman Hospital
Newcastle, Haematology, Newcastle, UK,
3
Freeman Hospital, Nuclear
Medicine, Newcastle, UK,
4
King's College Hospital, Nuclear Medicine,
London, UK
Background: Among patients with large Bcell lymphoma responding
to CD19 CART, about half will only have transient response and
relapse within 6 months of treatment. It is unclear which patient or
disease factors determine shortvs. longterm response to CART
and how to define suboptimal response requiring additional treat-
ment. We assessed early FDG PET response as predictor of outcome
after CD19 CART in lymphoma.
Methods: We analysed 90 patients with relapsed/refractory large B
cell lymphoma treated with licenced CD19 CART across 2 UK
centres (King's College Hospital London and Freeman Hospital
Newcastle) between February 2019 and December 2020 who were
evaluable for response at 1 and 3 months. Response was assessed
using the 5point Deauville score (DS) as per standard practice. The
median followup for living patients was 16 months.
Results: Of 90 infused patients, 71 (79%) were treated with axi-
cabtagene ciloleucel and 19 (21%) with tisagenlecleucel. Patients’
median age was 57 years (range 18 77). 55 (61%) had de novo
DLBCL, 29 (32%) transformed lymphoma, and 6 (7%) primary
mediastinal Bcell lymphoma. 64 (71%) had advance stage, 25
(28%) bulky disease, and 51 (57%) extranodal involvement at
baseline. 78/90 (86%) patients received bridging therapy prior to
CART.
66/90 (73%) of patients showed response to CART at the 1month
response assessment: 31 (33%) complete response (CR, DS 1: n =
10, DS 2: n =8; DS 3: n =13), and 35 (38%) partial response (PR, DS
4: n =27, DS 5: n =8). 2 (2%) patients had stable disease (SD) and 22
(25%) had progressive disease (PD) at 1 month. Deauville response
levels were not associated with the histological subtype, doublehit
status, stage/bulk at presentation, number of prior treatment lines,
response to last treatment, type of bridging therapy, or LDH and
ECOG PS preinfusion.
DS response categories at 1 month were significantly associated with
the risk of early progression at 3 months (p <0.0001): 22% for DS 1
2, 46% for DS 3, 33% DS 4 and 100% for DS 5 and patients with SD
(see figure). The 12months progressionfree survival (PFS) was 72%
(95% CI 5193) for patients with DS 12, 54% (95% CI 3970) for DS
34 and 0% for DS 5 (p <0.0001). Deauville response at 1 month
remained significant for PFS in multivariate analysis adjusting for
ECOG PS, LDH, stage, extranodal involvement and bulk. Overall
survival (OS) at 12 months for DS 12, DS 34, and DS 5 was 81%
(95% CI 6399), 64% (95% CI 4881), and 45% (95% CI 983),
respectively (p =0.097).
Discussion: Our results indicate that early PET response using
Deauville criteria may be used to predict the risk of CART failure
TABLE 1Clinical features of CAR Tcell related hematotoxicity by CAR Tcell product and by CARHEMATOTOX score. Statistical
significance between groups was determined by Fisher’s exact twosided t test
SUPPLEMENT ABSTRACTS
-
137
and to guide postCART management in lymphoma. While patients
achieving early DS 12 remission show excellent longterm outcomes,
patients with DS 34 might benefit from combination approaches
within clinical trials to increase the chance of ongoing remission.
Patients with DS 5 response had dismal outcome in our cohort and
should be regarded primary treatment failure for which early ther-
apeutic intervention might be warranted.
Keywords: PETCT
Conflicts of interests pertinent to the abstract
T. Menne
Consultant or advisory role: Kite/Gilead, Amgen, Novartis, Pfizer,
Celgene, Daiichi Sankyo, Atara
Honoraria: Kite/Gilead, Takeda, Janssen, Roche, Servier, Novartis
Research funding: Janssen, Astra Zeneca, Novartis
W. Osborne
Honoraria: Roche, Takeda, Pfizer, Servier, Kite Gilead, MSD, Novartis,
Beigene, AstraZeneca, Syneos, Autolus
P. Patten
Honoraria: Novartis and Kite/Gilead
R. Sanderson
Honoraria: Novartis and Kite/Gilead
A. Kuhnl
Honoraria: Novartis, and Kite
084 |FIRST RESULTS OF DLBCL PATIENTS TREATED WITH
CART CELLS AND ENROLLED IN DESCART REGISTRY, A
FRENCH REALLIFE DATABASE FOR CART CELLS IN
HEMATOLOGIC MALIGNANCIES
S. Le Gouill
1
, E. Bachy
2
, R. Di Blasi
3
, G. Cartron
4
, D. Beauvais
5
,
F. Le Bras
6
, FrançoisX. Gros
7
, S. Choquet
8
, P. Bories
9
, Marie
Thérès. Rubio
10
, RenéO. Casasnovas
11
, L. Bounaix
12
, M. Mohty
13
,
M. Joris
14
, T. Gastinne
1
, P. Sesques
2
, J. J. Tudesq
4
,
F. Morschhauser
5
, E. Gat
15
, F. Broussais
16
, C. Thieblemont
3
,
R. Houot
17
1
CHU de Nantes, Hematology, Nantes, France,
2
HCL, Hematology, Lyon,
France,
3
Höpital SaintLouis APHP, Hematology, PAris, France,
4
CHU de
Montpellier, Hematology, Montpellier, France,
5
CHU de Lille, Hematology,
Lille, France,
6
CHU Creteil, Hematology, Creteil, France,
7
CHU de
Bordeaux, Hematology, Bordeaux, France,
8
Hôpital La PitiéSalpetrière
APHP, Hematology, Paris, France,
9
Oncopole de Toulouse, Hematology,
Toulouse, France,
10
CHU de Nancy, Hematology, Nancy, France,
11
CHU
de Dijon, Hematology, Dijon, France,
12
CHU de ClermontFerrand, He-
matology, ClermontFerrand, France,
13
Hôpital SaintAntoine, Hematol-
ogy, Paris, France,
14
CHU Amiens, Hematology, Amiens, France,
15
LYSARC, DESCART, LYON, France,
16
LYSARC, Medical, Lyon, France,
17
CHU de Rennes, Hematology, Rennes, France
Background: DESCART is the French national registry for patients
treated with commercial CART cells (DLBCL and ALL). DESCART
has been designed by LYSA/LYSARC and aims to collect reallife
FIGURE 1 Outcome according to Deauville response at 1 months. (A) risk of progressions at 3 months, (B) Progressionfree
survival
138
-
SUPPLEMENT ABSTRACTS
data. DESCART was approved by the French authorities in 2019
and is the reference registry for CART cells reimbursement by
French health authorities. Data (patients’ characteristics, safety,
efficacy and longterm outcome…) from time of medical decision to
treat with CART cells to up to 15 years after CART cells infusion
are registered in DESCART. Several complementary registries are
also linked to DESCART database (immunemonitoring, blood and
tumor biobanking CeViCART, imagery platform). We present the
first analyses regarding DLBCL patients' characteristics and
outcome registered in DESCART.
Methods: All patients with DLBCL registered in DESCART were
eligible for the present study. All patients gave informent consent
befor DESCART registration.
Results: To date (Jan 2021), 14 out of 24 CART cells accredited
French centers have registered patients in DESCART (other centers
are being opened). The first patient was registered in December 2019.
At the time of the analysis, 537 DLBCL patients have been registered.
CART cells product has been ordered for 517 patients of whom 463
have been infused. At the time of registration in DESCART, median
age was 63.0 years (range, 5370), 40.6% of patients were >65yrs and
3.5% >75yrs. Lymphoma subtypes were DLBCL (91%), PMBL (3%),
and highgrade Bcell lymphoma (2%). Among patients for whom CAR
T cells have been ordered (n =517), 313 (60.5%) were male, 76 (14.7%)
had a PS2, 377 (72.9%) had an advanced disease (stage III or IV), 330
(63.8%) had elevated LDH. Median number of prior lines of treatment
was 3 (range, 2 3) and 21% of patients have been previously trans-
planted. Median time from CART cells order to infusion was 50 days
[range, 4360]. Median time from leukapheresis to CART infusion was
41.1 days (range, 3648). Overall, 65% of patients received Axicel and
35% received Tisaacel. Response was available in 419 infused pa-
tients. Best ORR was 70.2% (65.5% 74.5%). At D30 after CART cell
infusion, 157 (38%) patients achieved CR and 112 (27%) achieved PR.
Among the 157 patients who achieved a CR at D30, 96 (61%) remained
in CR at D90. The median followup calculated from CART cells order
was 7.4 months (range, 5.87.9) and 6m [range, 5.56.2] from CART
infusion. The median OS calculated from time of CART infusion is
12.7m [range, 10.6NA].
Summary/Conclusion: This first analysis from DESCART registry
seems to confirm CART cells efficacy in real life. Updated results
will be presented at the meeting. Overall, 537 DLBCL patients
have been registered in DESCART in 13 months. This demon-
trates that CART cells therapy has become a key treatment for R/
R DLBCL. In 2021, DESCART will be extended to MCL and
multiple myeloma.
EA previously submitted to EHA 2021.
Keywords: Aggressive Bcell nonHodgkin lymphoma, Cellular
therapies
Conflicts of interests pertinent to the abstract
S. Le Gouill
Consultant or advisory role: Gilead; Novartis
085 |EFFICACY AND SAFETY OF TISAGENLECLEUCEL (TISA
CEL) IN ADULT PATIENTS (PTS) WITH RELAPSED/REFRACTORY
FOLLICULAR LYMPHOMA (R/R FL): PRIMARY ANALYSIS OF THE
PHASE 2 ELARA TRIAL
N. H. Fowler
1
, S. J. Schuster
2
, M. Dickinson
3
, M. Dreyling
4
,
J. MartinezLopez
5
, A. Kolstad
6
, J. Butler
7
, M. Ghosh
8
, L. Popplewell
9
,
J. C. Chavez
10
, E. Bachy
11
, K. Kato
12
, H. Harigae
13
, M. José Kersten
14
,
C. Andreadis
15
, P. A. Riedell
16
, A. Zia
17
, M. C. Morisse
18
,
C. Thieblemont
19
1
MD Anderson Cancer Center, The University of Texas MD Anderson
Cancer Center, Houston, Texas, USA,
2
Perelman Center for Advanced
Medicine, University of Pennsylvania, Philadelphia, USA,
3
Clinical
Haematology, Peter MacCallum Cancer Centre and Royal Melbourne
Hospital, Melbourne, Australia,
4
Medizinische Klinik III, LMU Klinikum,
Munich, Germany,
5
Hospital 12 De Octubre Madrid, Complutense
University, CNIO, Madrid, Spain,
6
Department of Oncology, Oslo
University Hospital, Oslo, Norway,
7
Haematology and Bone Marrow
Transplantation, Royal Brisbane Hospital, Herston, Australia,
8
Department of Internal Medicine, Michigan Medicine University of
Michigan, Ann Arbor, USA,
9
Department of Hematology &
Hematopoietic Cell Transplantation, City of Hope National Medical
Center, Duarte, USA,
10
Department of Malignant Hematology, Moffitt
Cancer Center, Tampa, USA,
11
Department of Hematology, Hospices
Civils de Lyon and Université Claude Bernard Lyon 1, Lyon, France,
12
Department of Hematology, Kyushu University Hospital, Fukuoka,
Japan,
13
Department of Hematology, Tohoku University Hospital,
Sendai, Japan,
14
Cancer Center Amsterdam, Amsterdam UMC,
University of Amsterdam, on behalf of HOVON/LLPC, Amsterdam,
Netherlands,
15
Helen Diller Family Comprehensive Cancer Center,
University of California San Francisco, San Francisco, USA,
16
Department of Medicine, University of Chicago, Chicago, USA,
17
Biostatistics, Novartis Pharma AG, Basel, Switzerland,
18
Oncology,
Novartis Pharmaceuticals Corporation, East Hanover, USA,
19
Department of HematoOncology, Hôpital SaintLouisUniversité de
Paris, Paris, France
Introduction: Most pts with r/r FL experience multiple relapses and
progressively worse clinical outcomes with each line of therapy,
underlining a need for novel therapies. Tisacel has demonstrated
durable responses and manageable safety in adult pts with r/r diffuse
large Bcell lymphoma. Here we report the primary analysis of
ELARA (NCT03568461), an international, singlearm phase 2 trial of
tisacel in adult pts with r/r FL.
Methods: Eligible pts (18 y) had r/r FL (grades [Gr] 13A) after 2
lines of therapy or had failed autologous stem cell transplant.
Bridging therapy was permitted followed by disease assessment prior
to tisacel infusion. Pts received tisacel (0.6610
8
CAR+viable T
cells) after lymphodepleting chemotherapy. The primary endpoint
was complete response rate (CRR) by central review per Lugano
2014 criteria. Secondary endpoints included overall response rate
(ORR), duration of response (DOR), progressionfree survival (PFS),
SUPPLEMENT ABSTRACTS
-
139
overall survival (OS), safety, and cellular kinetics. Predefined primary
analysis occurred when 90 treated pts had 6 mo of followup.
Results: As of September 28, 2020, 98 pts were enrolled and 97
received tisacel (median followup, 10.6 mo). At study entry, median
age among treated pts was 57 y (range, 2973), 85% had stage IIIIV
disease, 60% had a FLIPI score 3, 65% had bulky disease, and 42%
had LDH >upper limit of normal. The median number of prior
therapies was 4 (range, 213); 78% of pts were refractory to their last
treatment (76% to any 2 prior regimens) and 60% progressed
within 2 y of initial antiCD20–containing treatment. Of 94 pts
evaluable for efficacy, the CRR was 66% (95% CI, 5675) and the
ORR was 86% (95% CI, 7892). CRRs/ORRs were comparable among
key highrisk subgroups. Estimated DOR (CR) and PFS rates at 6 mo
were 94% (95% CI, 8298) and 76% (95% CI, 6584), respectively. Of
97 pts evaluable for safety, 65% experienced Gr 3 adverse events
within 8 weeks postinfusion, most commonly neutropenia (28%) and
anemia (13%). Anygrade cytokine release syndrome (per Lee scale)
occurred in 49% of pts (Gr 3, 0%). Anygrade neurological events
(per CTCAE v4.03) occurred in 9% of pts (Gr 3, 0%; Gr 4, 1 pt and
recovered). Three pts died from progressive disease.
Cellular kinetic parameters for tisacel were estimated using trans-
gene levels (by qPCR) in peripheral blood. C
max
and AUC
028d
were
similar between responders (CR or partial response) and non
responders (stable or progressive disease). Maximum transgene
levels were reached by a median of 10 days in responders and 12.9
days in nonresponders; transgene persistence was detected up to
370 days and 187 days, respectively.
Conclusions: These data demonstrate the efficacy and acceptable
safety of tisacel in pts with r/r FL, including highrisk pts after
multiple lines of prior therapy, and suggest that tisacel may be a
promising therapy for pts with r/r FL.
EA previously submitted to ASCO 2021.
The research was funded by: Novartis
Keywords: Indolent nonHodgkin lymphoma, Cellular therapies
Conflicts of interests pertinent to the abstract
S. J. Schuster
Consultant or advisory role: Celgene, Nordic Nanovector, Novartis,
Abbvie, Acerta Pharma/AstraZeneca, Alimera Sciences, BieGene,
Juno Therapeutics, Luxo Oncology, Tessa Therapeutics, Genentech/
Roche
Honoraria: Novartis, Celgene
Research funding: Novartis, Pharmacyclics, Adaptive Bio-
technologies, Merck, Genentech/Roche, Celgene, Juno Therapeutics,
Abbvie, Incyte, TG Therapeutics, DTRM
M. Dickinson
Consultant or advisory role: Novartis, BMS, Gilead Sciences, Roche,
Janssen
Honoraria: Roche, Amgen, MSD, Janssen, BMS, Novartis
Research funding: Roche, Novartis, Takeda, Celgene, MSD
Educational grants: Roche
M. Dreyling
Consultant or advisory role: Acerta Pharma/AstraZeneca, Bayer/Vi-
tal, Celgene/Jazz, Gilead Sciences, JanssenCilag, Novartis, Roche,
BeiGene
Honoraria: Bayer Health, Celgene, Gilead Sciences, JanssenCilag,
Roche Pharma AG
Research funding: Celgene, JanssenCilag, Roche Pharma AG,
Abbvie
Educational grants: Celgene, JanssenCilag, Roche Pharma AG
J. MartinezLopez
Consultant or advisory role: Janssen, Novartis, BMS, Incite, Astellas,
Glaxo
Stock ownership: Altum Sequencing
Honoraria: Janssen, Novartis, BMS, Incite, Astellas, Glaxo
Research funding: BMS, Roche
A. Kolstad
Consultant or advisory role: Nordic Nanovector
Research funding: Merck, Nordic Nanovector
Educational grants: Nordic Nanovector
J. Butler
Consultant or advisory role: Novartis
Honoraria: Novartis
M. Ghosh
Research funding: Novartis, BMS
L. Popplewell
Honoraria: Roche, Pfizer
Educational grants: Novartis
J. C. Chavez
Consultant or advisory role: Kite/Gilead, Novartis, Bayer, Kar-
yopharm Therapeutics, Verastem, Pfizer, MorphoSys, TeneoBio,
Celgene, Juno Therapeutics
Honoraria: Kite/Gilead, Genentech, AstraZeneca, BeiGene
Research funding: Merck
E. Bachy
Consultant or advisory role: Roche, Incyte
Research funding: Takeda, Amgen
Other remuneration: Nonfinancial support: Roche, BeiGene, Cel-
gene, Incyte; Personal Fees: Roche, Janssen, Celgene, Novartis,
Gilead
K. Kato
Consultant or advisory role: Abbvie, AstraZeneca, Celgene, Chugai,
Janssen, Eisai, Novartis, Daiichi Sankyo
Honoraria: Takeda, MSD, KyowaKirin, Janssen, Celgene, Ono,
Mundi, DainipponSumitomo, BMS
Research funding: Chugai, Takeda, KyowaKirin, Abbvie, Eisai,
Novartis, Celgnene, Ono, Daiichi Sankyo
140
-
SUPPLEMENT ABSTRACTS
H. Harigae
Honoraria: BMS, Novartis, Chugai, Jansseb
Research funding: Astellas
M. José Kersten
Consultant or advisory role: Novartis, Kite/Gilead, Miltenyi Biotec,
Takeda
Honoraria: Novartis, Kite/Gilead, Roche
Educational grants: Novartis, Kite/Gilead, Roche, Celgene
C. Andreadis
Employment or leadership position: Genentech/Roche (Recipient is
an immediate family member)
Consultant or advisory role: Kite/Gilead, Karyopharm Therapeutics,
Atara Biotherapeutics, Incyte, TG Therapeutics, Epizyme
Stock ownership: Genentech/Roche (Recipient is an immediate family
member)
Research funding: Novartis, GSK, Amgen, Juno Therapeutics, Cel-
gene, Merck
Educational grants: Kite/Gilead
P. A. Riedell
Consultant or advisory role: Kite/Gilead, Celgene/BMS, MorphoSys
Takeda, Verastem, Karyopharm Therapeutics, Calibr, Bayer
Educational grants: Novartis
A. Zia
Employment or leadership position: Novartis
M. C. Morisse
Employment or leadership position: Novartis
N. H. Fowler
Consultant or advisory role: Genentech/Roche, TG Therapeutics,
Verastem, Bayer, Celgene, Novartis
Research funding: Roche, Celgene, Novartis, Gilead Sciences, TG
Therapeutics, Novartis, Abbvie, BeiGene
C. Thieblemont
Honoraria: Roche, Incyte, Novartis, Janssen, Bayer, Abbvie, Gilead
sciences, Celgene
Research funding: Roche
Educational grants: Roche, Novartis, Kite/Gilead, JanssenCilag
086 |TRANSCEND CLL 004: PHASE 1 COHORT OF
LISOCABTAGENE MARALEUCEL (LISOCEL) COMBINED WITH
IBRUTINIB (IBR) FOR PATIENTS (PTS) WITH R/R CLL/SLL
W. G. Wierda
1
, K. A. Dorritie
2
, J. Munoz
3
, D. M. Stephens
4
,
S. Solomon
5
, H. H. Gillenwater
6
, L. Gong
7
, L. Yang
8
, K. Ogasawara
9
,
J. Thorpe
10
, T. Siddiqi
11
1
The University of Texas MD Anderson Cancer Center, Department of
Leukemia, Division of Cancer Medicine, Houston, Texas, USA,
2
UPMC
Hillman Cancer Center, Division of Hematology/Oncology, Pittsburgh,
Pennsylvania, USA,
3
Banner MD Anderson Cancer Center, Department
of Lymphoma/Myeloma, Phoenix, Arizona, USA,
4
Hutsman Cancer
Institute, University of Utah, Salt Lake City, Utah, USA,
5
Immunotherapy Program, Northside Hospital Cancer Institute, Atlanta,
Georgia, USA,
6
Bristol Myers Squibb, Global Clinical Development,
Seattle, Washington, USA,
7
Bristol Myers Squibb, Clinical Research and
Development, Seattle, Washington, USA,
8
Bristol Myers Squibb, Global
Biometric and Data Science, Seattle, Washington, USA,
9
Bristol Myers
Squibb, Clinical Pharmacology and Pharmacometrics, Princeton, New
Jersey, USA,
10
Bristol Myers Squibb, Immunomodulatory therapies,
Seattle, Washington, USA,
11
City of Hope National Medical Center,
Department of Hematology & Hematopoietic Cell Transplantation,
Duarte, California, USA
Introduction: Lisocel is a CD19directed CAR T cell product
administered at equal target doses of CD8
+
and CD4
+
CAR
+
T
cells. We report updated safety and efficacy from the investiga-
tional phase 1 lisocel +ibr dose escalation cohort of the phase 1/
2 TRANSCEND CLL 004 study (NCT03331198) in pts with R/R
CLL/SLL.
Methods: Eligible pts with R/R CLL/SLL met 1 of the following:
progressed on ibr by enrollment; had highrisk features and were
on ibr for 6 months (mo) with <CR; had a BTK or PLCγ2gene
mutation; had previous ibr and no contraindication to reinitiating
it. At enrollment, pts started or continued ibr 420 mg/day through
leukapheresis and for 90 days after lisocel infusion. Pts received
lisocel infusion at 50 10
6
(dose level [DL]1) or 100 10
6
(DL2)
CAR
+
T cells after 3 days of lymphodepletion with fludarabine/
cyclophosphamide. Primary objectives for phase 1 were safety and
determining the recommended dose of lisocel when given with
ibr. Antitumor activity (ORR [CR +CR with incomplete blood
count recovery (CRi)] +PR) and cellular kinetics were exploratory
objectives.
Results: At data cutoff, 19 pts received lisocel (DL1, n =4; DL2, n
=15) with ibr. Median age was 61 (range, 5077) years, and 18
pts (95%) had highrisk cytogenetics (del[17p], n =8; TP53 mu-
tation, n =6; complex karyotype [3 chromosomal aberrations], n
=8). Pts had a median of 4 (range, 110) prior therapies. All pts
were R/R to prior ibr; 11 pts (58%) had disease refractory to ibr
and venetoclax. Two pts were treated as outpatients. No dose
limiting toxicities were observed at either DL. Most pts (n =15,
79%) experienced ibrrelated TEAEs; 7 (37%) were grade 3. Ibr
related TEAEs in 2 and 4 pts led to dose reductions and discon-
tinuations, respectively (Table). No grade 5 TEAEs occurred.
Cytokine release syndrome (CRS) was reported in 14 pts (74%),
with 1 grade 3 event; 6 (32%) reported neurological events (NEs; 3
grade 3). Eight pts (42%) received tocilizumab and/or cortico-
steroids to manage CRS and/or NEs. Preliminary cellular kinetics
data showed a median time to peak lisocel expansion of 11 days
(IQR, 10–15). Of 19 pts with 1mo followup, 18 (95%) had an
objective response; 12 (63%) had a CR/CRi. One pt (5%) had
stable disease. Responses were achieved by Day 30 postinfusion,
and 16 of 18 pts (89%) have ongoing responses at 6 mo. Of 19
pts evaluable for MRD, 17 (89%) achieved undetectable MRD in
SUPPLEMENT ABSTRACTS
-
141
blood via flow cytometry and 15 (79%) in bone marrow by next
generation sequencing (sensitivity of both, 10
–4
).
Conclusions: Preliminary data show that lisocel +ibr was asso-
ciated with manageable safety, including a low incidence of grade
3 CRS and NEs, and promising efficacy in heavily pretreated pts,
who were all R/R to prior ibr, with R/R CLL/SLL. No clear differ-
ence in safety was observed between DLs, and DL2 was selected
as the dose of lisocel when given with ibr in the ongoing
expansion cohort.
The research was funded by: This study was funded by Juno Thera-
peutics, a BristolMyers Squibb Company. All authors contributed to
and approved the abstract; writing and editorial assistance were
provided by Jeremy Henriques, PhD, of The Lockwood Group
(Stamford, CT, USA), funded by Bristol Myers Squibb.
Keywords: Chronic Lymphocytic Leukemia (CLL), Combination
Therapies, Immunotherapy
Conflicts of interests pertinent to the abstract
W. G. Wierda
Research funding: GSK/Novartis, Abbvie, Genentech, Pharmacyclics
LLC, Acerta Pharma Inc, Gilead Sciences, Juno Therapeutics, KITE
Pharma, Sunesis, Miragen, Oncternal Therapeutics, Cyclacel, Loxo
Oncology Inc., Janssen, Xencor
K. A. Dorritie
Consultant or advisory role: Juno/BMS, KiteGilead, Genentech/
Hoffman LaRoche, Janssen, Nordic Nanovector
J. Munoz
Consultant or advisory role: Pharmacyclics, Bayer, Gilead/Kite
Pharma, Pfizer, Janssen, Juno/Celgene, BMS, Kyowa, Alexion, Bei-
gene, Fosunkite, Innovent, Seattle Genetics
Honoraria: Kyowa and Seattle Genetics
Research funding: Bayer, Gilead/Kite Pharma, Celgene, Merck, Por-
tola, Incyte, Genentech, Pharmacyclics, Seattle Genetics, Janssen,
Millennium
Other remuneration: Gilead/Kite Pharma, Kyowa, Bayer, Pharma-
cyclics/Janssen, Seattle Genetics, Acrotech/Aurobindo, Beigene,
Verastem, AstraZeneca, Celgene/BMS, Genentech/Roche, AbbVie
D. M. Stephens
Consultant or advisory role: Beigene, Jannsen, Pharmacyclics, Epi-
zyme, Adaptive, TG Therapeutics, Karyopharm, Innate
Research funding: Karyopharm, Acerta, Arqule, Mingsight, Juno,
Gilead, Verastem
H. H. Gillenwater
Employment or leadership position: Bristol Myers Squibb
Stock ownership: Bristol Myers Squibb
TABLE 1Safety and Efficacy
142
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SUPPLEMENT ABSTRACTS
L. Gong
Employment or leadership position: Bristol Myers Squibb
Stock ownership: Bristol Myers Squibb
L. Yang
Employment or leadership position: Bristol Myers Squibb
K. Ogasawara
Employment or leadership position: Bristol Myers Squibb
Stock ownership: Bristol Myers Squibb
J. Thorpe
Employment or leadership position: Bristol Myers Squibb
Stock ownership: Bristol Myers Squibb
T. Siddiqi
Honoraria: Juno Therapeutics, Celgene, Bristol Myers Squibb, Phar-
macyclics LLC, an Abvie Company, Kite Pharma, AstaZeneca, Bei-
Gene, Janssen
Research funding: Funding to Institution: Juno Therapeutics, Celgene,
Pharmacyclics LLC, an Abvie Company, Kite Pharma, AstraZeneca,
BiGene, TG Therapeutics, Oncternal, Ascentage Pharma
087 |OUTCOME OF LARGE BCELL LYMPHOMA PATIENTS
FAILING CD19 TARGETED CART THERAPY
A. Kuhnl
1
, A. A. Kirkwood
2
, M. O'Reilly
3
, R. Sanderson
1
, E. Tholouli
4
,
A. Patel
5
, C. Besley
6
, S. Iyengar
7
, C. Jones
8
, A.L. Latif
9
, J. Norman
4
,
W. Osborne
10
, G. Collins
11
, A. McMillan
12
, K. Ardeshna
3
,
S. Chaganti
13
, T. Menne
10
1
King's College Hospital, Haematology, London, UK,
2
University College
London, CTC, London, UK,
3
University College London Hospital,
Haematology, London, UK,
4
Manchester Royal Infirmary, Haematology,
Manchester, UK,
5
The Christie Manchester, Haematology, Manchester,
UK,
6
University Hospital Bristol, Haematology, Bristol, UK,
7
Royal
Marsden Hospital, Haematology, London, UK,
8
Cardiff University Hospital,
Haematology, Cardiff, UK,
9
Queen Elizabeth University Hospital,
Haematology, Glasgow, UK,
10
Freeman Hospital, Haematology,
Newcastle, UK,
11
Oxford University Hospitals, Haematology, Oxford, UK,
12
Nottingham University Hospitals, Haematology, Nottingham, UK,
13
University Hospitals Birmingham, Haematology, Birmingham, UK
Background: Despite high initial response rates, most patients with
relapsed/refractory (r/r) large Bcell lymphoma receiving CD19 tar-
geted CART therapy will progress or relapse. There are limited data
available on postCART management and outcomes. We provide
detailed outcome analyses from a prospective national cohort of
lymphoma patients progressing after licenced CD19 CART.
Methods: We analysed consecutive patients with r/r large Bcell
lymphoma who received axicabtagene ciloleucel or tisagenlecleucel
between Feb 2019 Dec 2020 across 10 UK centres and were pri-
mary refractory or relapsed after infusion.
Results: Of 294 patients infused with CART, 153 (52%) progressed.
143 (93%) of progressions occurred within 6 months (m) of infusion,
79 (52%) after an initial response (30 CR, 49 PR). The median time to
progression was 2.4 m (IQR: 0.99 13.3), 3.2 m (IQR: 2.9 5.1) after
initial CR vs. 3.0 m (IQR: 2.4 3.1) after PR.
82/153 (54%) patients received further treatment: 10 radiotherapy
(RT) alone, 31 Rbendamustine/polatuzumab vedotin (RBP), 13 R
lenalidomide, 13 standard chemotherapies, 6 checkpoint inhibition
(CPI), 3 CD20xCD3 bispecific antibodies, 2 BTKi, 4 other treatments.
10 patients underwent allogeneic transplant.
Patients undergoing treatment for postCART relapse were younger
(med. age 56y vs. 60y; p =0.03), had better ECOG performance status
preinfusion (0/1: 96% vs. 76%; p =0.005), and more likely to have had
transient responses to CART (61% vs. 41%; p =0.007) compared to
patients not considered for further treatment.
With a median followup of 9.6 m, median OS post CART progres-
sion was 3.7 m (95% CI: 3 6), with 1.4 m (95% CI: 1 2) for patients
not receiving further treatment, and 7.8 m (95% CI: 6 10) for
treated patients [11.0 m for patients responding vs. 4.5 m for non
responders].
The overall response rate to postCART treatment was 39% (28/72)
and within groups of 10+patients as follows: 15/31 (48%) for RBP, 2/
13 (15%) for standard chemotherapy, and 2/11 (18%) for R
lenalidomide, with a median OS post progression of 10 m (95% CI:
8 12), 5.2 m (2 NR) and 7.3 m (3 NR), respectively.
18 (22%) patients achieved CR following postCART therapy (3 after
RT, 10 RBP, 2 CPI, 1 bispecific antibodies, 2 chemotherapy), 9 of
which underwent allogeneic transplant. Median OS after achieving
CR was 12.3 m (5 NR). Updated responseand survival data will be
provided at the meeting.
Discussion: This large national realworld cohort demonstrates the
poor outcome of lymphoma patients failing CD19 CART, with almost
half of patients not given further treatment. Response to postCART
therapies is limited indicating an area of unmet need in those fit for
further treatment and highlighting the importance of appropriate
patient counselling. Access to effective novel agents may increase the
numbers who can be bridged to allogeneic transplant and potentially
improve longterm outcomes.
Keywords: Aggressive Bcell nonHodgkin lymphoma, Cellular
therapies
Conflicts of interests pertinent to the abstract
A. Kuhnl
Consultant or advisory role: Kite, Novartis, Celgene
Honoraria: Kite, Novartis
Educational grants: Kite
A. A. Kirkwood
Consultant or advisory role: Kite
M. O'Reilly
Honoraria: Kite, Novartis
Educational grants: Kite, Novartis
R. Sanderson
Honoraria: Kite, Novartis
SUPPLEMENT ABSTRACTS
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143
E. Tholouli
Consultant or advisory role: Kite, Novartis
Honoraria: Kite, Novartis
A. Patel
Honoraria: Kite, Novartis
C. Besley
Honoraria: Kite, Novartis
S. Iyengar
Consultant or advisory role: Kite, Takeda, Beigene
Honoraria: Kite, Takeda
Educational grants: Abbvie
A.L. Latif
Honoraria: Kite, Jazz, Daiichi Sankyo, Novartis, Amgen, AbbVie,
Astellas
W. Osborne
Honoraria: Roche, Takeda, Pfizer, Servier, Kite Gilead, MSD, Novartis,
Beigene, Astra Zeneca, Syneos, Autolus
G. Collins
Consultant or advisory role: Kite
Honoraria: Kite, Novartis
A. McMillan
Consultant or advisory role: Roche
Honoraria: Roche
Educational grants: Roche
S. Chaganti
Honoraria: Kite, Novartis
T. Menne
Honoraria: Kite, Amgen, Novartis, Pfizer, Celgene, Daiichi Sankyo,
Atara, Takeda, Janssen, Roche, Servier
Research funding: Janssen, Astra Zeneca, Novartis
16ICML SPECIAL LECTURE: LYMPHOMA TREAT-
MENT IN DEVELOPING COUNTRIES
088 |LYMPHOMA TREATMENT IN DEVELOPING COUNTRIES
A. Biondi
1
1
Found. MBBM / San Gerardo Hospital, Pediatric Clinic, Univers. Milano
Bicocca, Monza (Italy)
Over the last 30 years numerous pediatric oncology programs have
been established in Low Middle Income Countries (LMIC) through
international cooperation projects. Treatment of lymphomas faced
major challenges in diagnostics requirements (pathology and imaging)
and shortage of chemotherapeutic agents and of support therapy,
with need of protocols adaptation to local situations. Projects for
Burkitt Lymphoma, facilitated by the biological features of the
disease, have been quite successful since the beginning in different
geographical areas, and particularly in Africa, where this lymphoma is
endemic. These initiatives were coordinated by the International
Society of Pediatric Oncology (SIOP), the French African Group of
Pediatric Oncology (GFAOP) and other organizations.
The Center of Pediatric HematoOncology of Monza, together with
the Pediatric Oncology Department of the Istituto Tumori of Milano
(INT), the Associazione Medica per l’aiuto al Centro America (AMCA,
Bellinzona, Switzerland) and SJCRH (USA) has pioneered Pediatric
Oncology in Nicaragua and Central America, where the Pediatric
HematoOncology Association of Central America (AHOPCA) was
instituted, to develop common treatment strategies and protocols to
diagnose and treat most common childhood malignancies in the
whole area.
Hodgkin Disease (HD) was treated initially in the early 90ies in
Nicaragua and subsequently in the AHOPCA Countries with COPP
COPP/ABV courses; staging was done with Xrays and ultrasound only;
radiation therapy (RT) was not available. Results of the AHOPCA LH
1999 protocol in 216 eligible patients showed that abandonment rate
was 14%; treatment was well tolerated; EFS at 5 and 10 years was 71%
and 68% respectively. The subsequent AHOPCA LH 2004 protocol
used ABVD courses for favorable disease and OEPA COPDac courses
for the high risk group and limited RT. The 5year EFS and Survival in
933 patients evaluable were 72.3% and 81.3%, with abandonment
considered event or 79.9% and 87.4% when abandonment was
censored. This experience served to generate the CLEHOP LH proto-
col, which is now used in many Countries of Latin America.
Burkitt Lymphoma has been treated with a modified reduced in-
tensity NHL BFM90 regimen. Despite an Induction death rate of
8.8% and an abandonment rate of 6%, a 3 years EFS of 70% was
achieved in 386 eligible patients diagnosed in the period 2004
2016. Currently a new study is ongoing with better control of diag-
nostic accuracy including genetics.
Patients with LACL have been treated with different protocols (APO,
a Protocol designed for TALL, a modified BFM protocol) with an
overall 5year EFS of 67%. Lymphoblastic lymphomas are generally
treated with modified ALL protocols. Although no reports on
outcome in these patients are available, it should be slightly superior
to that of ALL, for which a long term EFS close to 50% is obtained.
The disadvantage in this disease is the need of longer treatment
duration, which is associated with toxicity deaths and high rates of
abandonment.
Overall these experiences show that, despite the diagnostic and im-
aging limitations, childhood lymphomas can be treated successfully in
LMIC if there is a local commitment. The major challenges are the
accuracy of the diagnosis, availability of antineoplastic agents and
support therapy. Global medicine programs can play a key role to
improve these outcomes, in keeping with the recommendations and
commitment by the WHO too.
Keywords: Therapeutics and Clinical Trials in Lymphoma
No conflicts of interests pertinent to the abstract.
144
-
SUPPLEMENT ABSTRACTS
DOI: 10.1002/hon.2880
SUPPLEMENT ABSTRACTS
EPOSTERS
LYMPHOMA BIOLOGY
089 |CLINICAL IMPACT OF TCELL RECEPTOR REPERTOIRE
DIVERSITY IN PATIENTS WITH LYMPHOMA UNDERGOING
AUTOLOGOUS STEM CELL TRANSPLANTATION
G. Ø. Jørgensen
1
, F. Favero
2
, J. Schmidt Jespersen
2
, M. R. Tulstrup
1
,
F. G. RodriguezGonzalez
2
, A. F. Nielsen
3
, B. Sørensen
4
, L. H. Ebbe-
sen
5
, J. Bæch
6
, E. K. Haastrup
3
, C. Nielsen
7
, Pär L. Josefsson
1
,
M. Thorsgaard
8
, T. C. ElGalaly
9
, P. Brown
1
, J. L. Weischenfeldt
2
,
T. S. Larsen
10
, K. Grønbæk
1
, S. Husby
1
1
Rigshospitalet, Hematology, Copenhagen N, Denmark,
2
Finsen
laboratory, HematologyOncology, Rigshospitalet, Copenhagen, Denmark,
3
Rigshospitalet, Dept. of Clinical Immunology, Copenhagen, Denmark,
4
Aarhus University Hospitalet, Clinical Immunology, Aarhus, Denmark,
5
Aarhus University Hospital, Clinical Immunology, Aarhus, Denmark,
6
Aalborg University Hospital, Clinical Immunology, Aalborg, Denmark,
7
Odense University Hospital, Dept. of Clinical Immunology, Copenhagen,
Denmark,
8
Aarhus University Hospital, Hematology, Aarhus, Denmark,
9
Aalborg University Hospital, Aalborg, Aalborg, Denmark,
10
Odense Uni-
versity Hospital, Hematology, Odense, Denmark
The adaptive immune response, and especially the role of Tcells has
become a key focus in the treatment of lymphoma. The Tcell re-
ceptor (TCR) is exclusive for every Tcell clone and thus provides
unique information about the condition of the immune system. Novel
NGS sequencing has made it possible to identify hundred thousands
of Tcell clones in a single sample, consequently termed the TCR
repertoire. Poorer diversity of the TCR repertoire has been associ-
ated with inferior outcomes in other cancers [Thommen DS et al.
Cancer Cell 2018]. We explored how the systemic Tcell diversity
impacted the longterm outcomes in lymphoma patients undergoing
highdose chemotherapy and autologous stem cell transplantation
(ASCT).
We performed highthroughput RNA based sequencing of the V,
D and J segment of TCR beta chain with the Illumina Immune
Repertoire NGS panel. In 288 patients with aggressive lymphoma
(predominantly Bcell NHL), we have sequenced the circulating TCR
repertoire in the autologous harvest products used in the ASCT. All
patients were included in a nationwide Danish cohort with full long
term followup data on survival, infections, transfusion history and
secondary cancers [Husby S et al. Leukemia 2020]. By using the
MiXCR and Immunarch bioinformatic pipelines we analyzed the TCR
repertoire diversity, as measured by the Chao1 estimation, and used
FIGURE 1
© 2021 The Authors. Hematological Oncology published by John Wiley & Sons Ltd.
Hematological Oncology. 2021;39(S2):145383. wileyonlinelibrary.com/journal/hon
-
145
the median value in the cohort as a cutoff for high and low TCR
repertoire diversity, respectively.
As of March 2021, analysis of 92 patients had been finalized.
Patients older than 60 years had a significantly lower TCR repertoire
diversity compared to younger (p =0.03, Wilcoxon rank sum test).
There was no association between lymphoma subtype and TCR
repertoire diversity. In a KaplanMeier survival analysis we found a
trend towards longer overall survival in patients with high TCR
repertoire diversity (Figure 1).
Detailed profiling of the TCR repertoire coupled with long
term followup of patients undergoing ASCT may provide novel
information regarding the impact of the patient's own adaptive
immune response on treatment efficacy. A dysfunctional Tcell
repertoire can furthermore have implications for selection of pa-
tients to undergo cellular therapies (ie. ASCT or CAR Tcell
treatment) in contrast to noncellular therapies (i.e. bispecific an-
tibodies, small molecule inhibitors). Full analysis of all 288 patients
and correlation with posttransplant infections, transfusions and
secondary cancers are ongoing and will be presented at the
16ICML.
The research was funded by: Rigshospitalets Research Fund and
The Capital Region Denmark Research Fund.
Keywords: Tumor Biology and Heterogeneity, Diagnostic and Prog-
nostic Biomarkers, Stem Cell Transplant
No conflicts of interest pertinent to the abstract.
090 |BASELINE CIRCULATING TUMOUR DNA AND TOTAL
METABOLIC TUMOUR VOLUME AS EARLY OUTCOME
PREDICTORS IN AGGRESSIVE BCELL LYMPHOMA. A REAL LIFE
PROSPECTIVE 112PATIENT COHORT
E. Le Goff
1
, P. BlancDurand
2
, L. Roulin
1
, R. Loyaux
3
, D. L. MBoum-
bae
3
, E. Poullot
4
, C. Robe
4
, I. Benmaad
3
, G. Gricourt
5
, A. Aissat
5
,
C. CopieBergman
4
, F. Lemonnier
1
, P. Gaulard
4
, E. Itti
2
, C. Haioun
1
,
M.H. Delfau Larue
3
1
Assistance Publique Hôpitaux de Paris, APHP, University Hospital Henri
Mondor, Lymphoid malignancies unit, Creteil, France,
2
Assistance Publique
Hôpitaux de Paris, APHP, University Hospital Henri Mondor, Nuclear
medicine, Creteil, France,
3
Assistance Publique Hôpitaux de Paris, APHP,
University Hospital Henri Mondor, hematobiology and Immunobiology
Department, Creteil, France,
4
Assistance Publique Hôpitaux de Paris, APHP,
University Hospital Henri Mondor, Pathology department, Creteil, France,
5
Assistance Publique Hôpitaux de Paris, APHP, University Hospital Henri
Mondor, Bioinformatics department, Creteil, France
Introduction: The addition of rituximab to CHOP chemotherapy
(RCHOP) has improved the outcome of patients with aggressive
Bcell lymphoma. However, depending on their specific adverse
prognostic factors, approximately 30 to 40% have a poor outcome.
Besides the International Prognostic Index (IPI), circulating cell free
tumour DNA (CtDNA) load and baseline total metabolic tumour
volume (TMTV) have been shown to predict progressionfree survival
(PFS) and survival, mostly in retrospective studies. The aim of this
study was to evaluate the combined prognostic value of CtDNA and
TMTV at diagnostic in a prospective “real life” cohort of previously
untreated aggressive Bcell lymphoma.
Methods: Clinical features, plasma sampling and FDG PET/CT of
consecutive patients diagnosed with aggressive Bcell lymphoma
between 2017 and 2020 were collected in a single institution. Next
generation sequencing of the 36 Lymphopanel targeted Bcell lym-
phoma gene was performed on CfDNA, and CtDNA load calculated
(Bohers et al., Blood Cancer J 2018). TMTV was calculated using fully
automatic segmentation of lymphoma lesions by artificial intelligence
(BlancDurand et al., EJNMMI 2020). Optimal cutoffs of CtDNA and
TMTV to predict PFS were determined by ROC and xTile analyses.
Results: We included 112 patients with aggressive Bcell lymphoma:
87 diffuse large Bcell lymphoma, 7 highgrade Bcell lymphoma, 5
primary mediastinal Bcell lymphoma and 3 others, of whom 79 had a
paired biopsy analysis. Median age was 63 years (2091), 83% pa-
tients had stage III/IV disease and 54% had elevated IPI (35).
Regarding Hans status, 52% were nongerminal center (nonGC). All
patients received RCHOP/CHOPlike chemotherapy, with central
nervous system prophylaxis in 49. CtDNA was detected in CfDNA in
95/112 patients (85%) with a median of 3.15 LOG haplotype equiv-
alent genome per mL (extremes 1.45 LOGhEG/mL). TMTV was
available in 102 patients with a median of 501 mL (extremes 45151
mL). With a median followup of 14 months, a significantly lower 1
year PFS was observed in patients with a high (>3.8 LOGhEG/mL)
CtDNA load (45% vs. 81%, P =0.002, HR =2.6 [1.167.28]) and with
a high (>200 mL) TMTV (64% vs. 97%, P =0.01, HR =3.56 [1.64
7.73]). Patients with both high CtDNA and TMTV values (highhigh)
had a lower 1year PFS than those with discrepant or both low values
(lowlow): 1year PFS estimates were 45% vs. 75% vs. 97%, respec-
tively (P =0.001, Figure 1). In multivariate Cox analysis including
146
-
SUPPLEMENT ABSTRACTS
Hans status, IPI, CtDNA and TMTV, only an elevated IPI (P =0.02)
and high CtDNA load (P =0.04) remained significant.
Conclusion: Despite a limited followup, this institutional study
conducted in a large cohort of patients with aggressive Bcell lym-
phoma treated in real life, emphasizes that high CtDNA load and high
TMTV are strong predictors of poor outcome. These characteristics
at baseline could help tailoring therapy in these patients.
Keywords: Diagnostic and Prognostic Biomarkers, PETCT, Liquid
biopsy
No conflicts of interest pertinent to the abstract.
091 |CIRCULATING TUMOR DNA LOAD AND TOTAL
METABOLIC TUMOR VOLUME IN DIFFUSE LARGE B CELL
LYMPHOMA (DLBCL) PATIENTS TREATED BY RCHOP FROM
REMARC, A LYSA STUDY
E. Bohers
1
, M. DelfauLarue
2
, L. Vercellino
3
, A. Cottereau
4
, M.
Viennot
1
, P. Viailly
1
, G. Salles
5
, H. Tilly
6
, G. Damaj
7
, C. Haioun
8
, V.
Ribrag
9
, F. Morschhauser
10
, R. Casasnovas
11
, E. NicolasVirelizier
12
,
P. Feugier
13
, R. Bouabdallah
14
, G. Cartron
15
, L. Renaud
16
, L. Chart-
ier
17
, C. Portugues
17
, M. Meignan
18
, F. Jardin
1
, C. Thieblemont
19
1
Team Genetics and Biomarkers in Lymphoma and Solid Tumors, INSERM
U1245, Normandy University, Rouen, France,
2
Hematobiology and
Immunobiology Department, INSERM U955 Eq9, APHP, University
Hospital Henri Mondor, Créteil, France,
3
Department of Nuclear Medicine,
APHP, SaintLouis Hospital, Paris, France,
4
Department of Nuclear Medi-
cine, APHP, Cochin, Paris, France,
5
Memorial Sloan Kettering Cancer Cen-
ter, Lymphoma Department, New York, New York, USA,
6
Department of
Hematology, Henri Becquerel Center, Rouen, France,
7
Department of He-
matology, Caen University Hospital, Caen, France,
8
Department of Hema-
tology, Henri Mondor University Hospital, Créteil, France,
9
Department of
Hematology, Gustave Roussy Institute, Villejuif, France,
10
Department of
Hematology, Lille University Hospital, Lille, France,
11
Department of He-
matology, Dijon University Hospital, Dijon, France,
12
Department of He-
matology, Leon Berard Center, Lyon, France,
13
Department of Hematology,
Nancy university Hospital, VandoeuvrelesNancy, France,
14
Department
of Hematology, Paoli Calmette Institute, Marseille, France,
15
Department of
Hematology, Montpellier University Hospital, Montpellier, France,
16
Department of Hematology, Lille University Hospital, Lille, France,
17
LYSARC, Lyon Hospital, PierreBenite, France,
18
Department of Nuclear
Medicine, APHP, University Hospital Henri Mondor, Creteil, France,
19
Department of Hematology, APHP, SaintLouis Hospital, Paris, France
Background: Circulating tumor DNA (ctDNA) quantification has been
shown to predict therapeutic benefit in patients (pts) with DLBCL. We
recently investigated the prognostic impact of total metabolic tumor
volume (TMTV) in DLBCL pts responder to RCHOP in the REMARC
study. In the present ancillary study, we wish to analyze the potential
correlation of ctDNA with the outcome and relate these results to
functional imaging by PET/CT (TMTV). We also aim to correlate the
circulating tumor DNA load with the new score TMTV plus ECOG PS.
Patients and Methods: 794 pts were included in the study either at
diagnosis (n =446) or at the end of RCHOP (n =347). At the end of
RCHOP, 650 pts achieved a complete response and were random-
ized to receive 2 years of lenalidomide or placebo. Tumoral cfDNA
measurements were performed using a dedicated 36 genes panel
with the QiaSeq® technology. CtDNA concentrations were
expressed in haploid genome equivalents per mL of plasma (hGE/mL)
and calculated by multiplying the mean variant allele frequency (VAF)
by the concentration of total cfDNA (Bohers et al. Blood Cancer J
2018).The optimal ctDNA cutoffs for PFS and OS were determined
by Xtile analyses and confirmed by a training validation method.
Results: A total of 240 pts were analyzed, including 62 nonresponder
and nonrandomized pts (NRNRP) and 173 responder and random-
ized pts (REMARC pts). 5 pts had no interpretable ctDNA analysis and
were excluded.
Among the 235 NRNRP/REMARC cohort, a ctDNA >3.74 was
present in 14% of pts and was predictive for PFS (HR =1.68, 95%CI
1.02–2.76, p =0.0397) and OS (HR =2.15, 95%CI 1.283.61,
p=0.0031). The 3yPFS for pts with a ctDNA >3.74 was 47.3% (95%
CI: 30%63%) vs 71.5% (95% CI: 65%77%) for pts with a ctDNA
3.74. The 3yOS for pts with a ctDNA >3.74 was 56.4% (95%CI:
38%71%) vs 81.8% (95% CI: 76%87%) for pts with a ctDNA 3.74.
Among the 173 RCHOP responder patients (REMARC cohort),
the 12 monthsrelapse free survival since last cycle of RCHOP for pts
with a ctDNA >3.74 at diagnosis was 61.1% (95%CI: 35%79%) vs
88.7% (95%CI: 82%93%) for pts with a ctDNA 3.74 (p =0.009).
However, a ctDNA >3.74 was not predictive either for PFS (HR =1.64,
95%CI: 0.843.21, p =0.14) nor for OS (HR =1.91 95%CI: 0.933.89, p
=0.07). Among the 100 pts with ctDNA and TMTV available, median
log ctDNA was found significantly higher in TMTV >220 (n =58) vs
TMTV <220 (p =0.002). However, no significant impact of ctDNA
(threshold 3.4) and TMTV(threshold 220) was observed on PFS and OS.
Conclusion: Using a routinely targeted sequencing panel for ctDNA
measurement, we confirmed the prognostic value of ctDNA con-
centration to predict outcome in DLBCL patients. For patients
responding to RCHOP, high ctDNA level was significantly associated
with high TMTV and early relapse.
The research was funded by: BMS
Keywords: Diagnostic and Prognostic Biomarkers, Aggressive Bcell
nonHodgkin lymphoma
No conflicts of interest pertinent to the abstract.
092 |HIGH RISK AGGRESSIVE BCELL LYMPHOMA ON THE
LIQUID BIOPSY
L. Meriranta
1
, A. Alkodsi
1
, A. Pasanen
1
, M. Lepistö
2
, Y. N. Blaker
3
,
J. Jørgensen
4
, P. Mapar
5
, M. Björkholm
6
, M. Jerkeman
7
, H. Holte
3
,
E. Pitkänen
5
, P. Ellonen
8
, S. Leppä
1
1
University of Helsinki and Helsinki University Hospital Comprehensive
Cancer Centre, Department of Oncology and Applied Tumor Genomics
Research Program, Helsinki, Finland,
2
University of Helsinki, Institute for
SUPPLEMENT ABSTRACTS
-
147
Molecular Medicine Finland, Helsinki, Finland,
3
Oslo University Hospital,
Department of Oncology, Oslo, Norway,
4
Aarhus University Hospital,
Department of Hematology, Aarhus, Denmark,
5
University of Helsinki,
Institute for Molecular Medicine Finland, HiLIFE & Applied Tumor Geno-
mics Research Program, Helsinki, Finland,
6
Karoliska Institutet, Depart-
ment of Medicine, Stockholm, Sweden,
7
Lund University, Department of
Oncology, Lund, Sweden,
8
University of Helsinki, Institute for Molecular
Medicine Finland, Helsinki, Finland
Introduction: Inadequate molecular recognition of highrisk diffuse
large Bcell lymphoma (DLBCL) hampers the discovery of novel
treatments for the patients with poor outcome. We aimed to delin-
eate molecular determinants of outcome within the ctDNA of the
patients with aggressive Bcell lymphoma.
Methods: We applied wholegenome and targeted unique molecular
identifier corrected sequencing to serially sampled plasma cellfree
DNA of 101 patients less than 65 years with highrisk (aaIPI 23
and/or sitespecific risk factors for central nervous system (CNS)
progression) aggressive Bcell lymphoma (Figure 1A). The patients
were treated in a Nordic Lymphoma Group (NLG) phase II trial with
dosedense immunochemotherapy and early CNS prophylaxis (Leppä
et al., Blood Advances 4(9):19061915, 2020).
Results: We found that the patients with high pretreatment ctDNA
burden (log hGE/ml) were at high risk of relapse and early death from
lymphoma (Figure BC). In contrast, nonlymphoma related treat-
ment failures were mainly seen in the patients with low to moderate
ctDNA levels. High ctDNA burden overcame the conventional mea-
sures of high tumor burden and other highrisk features including
doublehit lymphomas.
Chemorefractory disease exhibited diverging ctDNA kinetics
during therapy, whereas late molecular responses, and endof
treatment negativity for minimal residual disease characterized
cured patients (Figure 1D). As a proofofconcept, we show that
advanced ctDNA tools based on hypermutation patterns and frag-
mentation pattern disparities can complement prediction of pro-
gression at the end of therapy, and provide tools to clinical
challenges, including false residual PET positivity.
Lastly, we analyzed the potential of noninvasive ctDNA inter-
rogation for somatic drivers, hypermutation signatures and variant
haplotypes to offer novel translational information for diagnostics
and understanding of treatmentrefractoriness in patients with
aggressive Bcell lymphoma. Genomic dissection of pretreatment
ctDNA revealed a strong association between TP53loss and high
ctDNA burden a duo that in the context of highrisk biology
rendered lymphomas refractory to frontline treatment. In contrast,
subclonal MYC lesions that were not detectable at diagnosis were
positively selected at late relapses following complete responses to
the initial therapy. We further identified that the limitations of tissue
biopsies can culminate in diagnosischanging discoveries in plasma
ctDNA, including progressiondriving transformation to highgrade
Bcell lymphoma.
FIGURE 1 Circulating tumor DNA in the NGL phaseII trial. A) Sample collection. B) Pretreatment ctDNA burden and response to
theraphy. CD) Survival according to (C) pretreatment ctDNA burden, and (D) ctDNAbased detection of molecular residual disease (MRD) in
posttreatment sample
148
-
SUPPLEMENT ABSTRACTS
Conclusions: Our integrative approach with prospectively collected
serial plasma samples reveals that quantitative, mutational and
fragmentation pattern features of ctDNA can be utilized as novel
diagnostic and prognostic tools in aggressive Bcell lymphomas.
EA previously submitted to EHA 2021.
The research was funded by: Academy of Finland, Finnish Cancer Or-
ganizations, Southern Finland National Cancer Center, Sigrid Juselius
Foundation, Helsinki University Hospital, Nordic Cancer Union
Keywords: Tumor Biology and Heterogeneity, Diagnostic and Prog-
nostic Biomarkers, Aggressive Bcell nonHodgkin lymphoma
No conflicts of interest pertinent to the abstract.
093 |IMMUNE AND VIRUSSPECIFIC RESPONSES IN
PARTICIPANTS WITH PRIMARY EFFUSION LYMPHOMA
RECEIVING LENALIDOMIDE, DOSEADJUSTED EPOCH, AND
RITUXIMAB (EPOCHR
2
)
K. Lurain
1
, R. Roshan
2
, R. Ramaswami
1
, R. Mangusan
1
, A. Widell
1
,
I. Ekwede
1
, J. M. Ziegelbauer
1
, T. S. Uldrick
3
, D. Whitby
2
,
R. Yarchoan
1
, L. T. Krug
1
1
National Cancer Institute, HIV and AIDS Malignancy Branch, Bethesda,
Maryland, USA,
2
Frederick National Laboratory for Cancer Research, Viral
Oncology Section, AIDS and Cancer Virus Program, LeidosBiomedical,
Frederick, Maryland, USA,
3
Fred Hutchinson Cancer Research Center,
Division of Global Oncology, Department of Medicine, Seattle, Washing-
ton, USA
Background: Primary effusion lymphoma (PEL) is an aggressive HIV
associated B cell lymphoma caused by Kaposi sarcoma herpesvirus
(KSHV, human herpesvirus 8). We presented safety data of a pro-
spective phase 1 of doseadjusted etoposide, vincristine, doxorubicin,
cyclophosphamide, and prednisone with rituximab and lenalidomide
(EPOCHR
2
) in untreated PEL at the ASH Annual Meeting 2020
(Abstract 2105). 6 HIV
+
cisgender men received antiretroviral ther-
apy, lenalidomide 25 mg days 110, and EPOCHR for 6 cycles. 3
participants (pts) had complete responses (responders); 3 had pro-
gressive/stable disease (nonresponders) at endoftreatment (EOT).
Methods: We performed flow cytometry evaluating T cell subsets,
monocytes (monos), and neutrophils at baseline (BL), postcycle 1
(C1), postcycle 4 (C4), EOT, and 1year postEOT (YR1). KSHV and
CMV/EBV/influenzaspecific T cell responses were measured using
an interferongamma (IFNg) ELISPOT assay at BL, EOT, and YR1.
We determined breadth of virusspecific responses by the number of
KSHV open reading frames (ORFs) eliciting IFNg responses and in-
tensity of responses by mean spot forming units (SFUs) per 10
6
PBMCs. Comparisons were evaluated by Wilcoxon rank sum and
Spearman correlation.
Results: At BL, responders had a higher percentage of inflammatory
tissue factor (TF)
+
CD14
+
monos compared with nonresponders
(median [med] 30% vs 10%, p =0.049), higher percentage of PD1
+
SUPPLEMENT ABSTRACTS
-
149
CD4
+
effector memory (CD27
CD45RO
+
) T (TEM) cells (med 90% vs
71%, p =0.049), and lower percentage of CD38
+
CD8
+
TEM cells
(med 75% vs 96%; p =0.049). Responders had a decrease in TF
+
CD14
+
monos from BL to C1 and C4 (p =0.049 and 0.049) and
decrease in PDL1
+
CD14
+
monos from BL to C1 (p =0.049)
compared to nonresponders. PDL1 expression on monos and neu-
trophils was strongly correlated (r =0.74), and TF and PDL1
expression on monos was correlated (r =0.45) when analyzing
EOT and YR1 changes from BL. KSHV ORF reactivity was variable
across pts with no differences in breadth or intensity between
response groups. KSHVspecific responses strongly correlated with
EOT and YR1 changes from BL in CD8 counts (r =0.86) and nega-
tively correlated with EOT and YR1 changes from BL in PDL1
expression on monos and neutrophils (r =0.57 and 0.69).
Conclusions: TF
+
and PDL1
+
expression on monos and PD1
+
expression on CD4
+
TEM cells may predict treatment outcomes in
pts with PEL receiving EPOCHR
2
. More data are needed to under-
stand how virusspecific responses affect outcomes. Immune re-
sponses will be further evaluated in an ongoing phase 2.
The research was funded by: the Intramural Research Program of the
NIH, National Cancer Institute and by US federal funds from the
National Cancer Institute, National Institutes of Health, under Con-
tract No.HHSN261200800001E.
Keywords: Diagnostic and Prognostic Biomarkers, Aggressive Bcell
nonHodgkin lymphoma, Combination Therapies
Conflicts of interests pertinent to the abstract
K. Lurain
Research funding: BMSCelgene through CRADA with the NCI
R. Ramaswami
Research funding: BMSCelgene through CRADA with the NCI
T. S. Uldrick
Research funding: BMSCelgene through CRADA with the NCI
Other remuneration: Coinventor on US Patent 10,001,483
D. Whitby
Other remuneration: Coinventor on US Patent 10,001,483
R. Yarchoan
Research funding: BMSCelgene through CRADA with NCI
Other remuneration: Coinventor on US Patent 10,001,483
094 |CLINICAL RESPONSES TO ODRONEXTAMAB
(REGN1979): CORRELATION WITH LOSS OF CD20 EXPRESSION
AS A POTENTIAL MECHANISM OF RESISTANCE AND BASELINE
BIOMARKERS OF TUMOR T CELLS
J. BrouwerVisser
1
, N. Fiaschi
2
, R. P. Deering
2
, A. Dhanik
3
, K. J.
Cygan
3
, W. Zhang
4
, S. Jeong
2
, S. Pourpe
2
, L. Boucher
2
, S. Hamon
1
, M.
S. Topp
5
, R. Bannerji
6
, J. Duell
5
, R. H. Advani
7
, D. M. Flink
8
, A.
Chaudhry
9
, A. Sirulnik
10
, I. Lowy
11
, A. J. Murphy
12
, D. M. Weinreich
13
,
G. D. Yancopoulos
14
, G. Thurston
15
, S. R. Ambati
16
, V. Jankovic
1
1
Regeneron Pharmaceuticals, Inc, Precision Medicine, Tarrytown, New
York, USA,
2
Regeneron Pharmaceuticals, Inc, Oncology and Angiogenesis,
Tarrytown, New York, USA,
3
Regeneron Pharmaceuticals, Inc, VI Next,
Tarrytown, New York, USA,
4
Regeneron Pharmaceuticals, Inc, Molecular
Profiling and Data Science, Tarrytown, New York, USA,
5
Universitätsklinikum Würzburg, Department of Internal Medicine 2,
Würzburg, Germany,
6
Rutgers Cancer Institute of New Jersey, Division of
Blood Disorders, New Brunswick, New Jersey, USA,
7
Stanford University,
Department of Medicine, Stanford, California, USA,
8
Regeneron
Pharmaceuticals, Inc, Global Development, Tarrytown, New York, USA,
9
Regeneron Pharmaceuticals, Inc, Hematology, Tarrytown, New York, USA,
10
Regeneron Pharmaceuticals, Inc, Global Clinical Development,
Tarrytown, New York, USA,
11
Regeneron Pharmaceuticals, Inc, Translation
Science and Oncology, Tarrytown, New York, USA,
12
Regeneron
Pharmaceuticals, Inc, Research, Tarrytown, New York, USA,
13
Regeneron
Pharmaceuticals, Inc, Head of Global Clinical Development, Tarrytown,
New York, USA,
14
Regeneron Pharmaceuticals, Inc, Chief Scientific Officer,
Tarrytown, New York, USA,
15
Regeneron Pharmaceuticals, Inc, Oncology
Research, Tarrytown, New York, USA,
16
Regeneron Pharmaceuticals, Inc,
Clinical Sciences Hematology, Tarrytown, New York, USA
Introduction: Odronextamab (REGN1979) is a fully human CD20
CD3 bispecific antibody being evaluated in patients (pts) with
relapsed/refractory Bcell nonHodgkin lymphoma (R/R BNHL). At
selected doses, odronextamab has demonstrated durable response
rates in pts with R/R follicular lymphoma (FL: 90%), and R/R diffuse
large Bcell lymphoma (DLBCL: 60%). Tumor biopsies from a Phase
1 study (NCT02290951) were analyzed to investigate the association
of Band Tcell biomarkers with initial clinical response and with
instances of subsequent progression.
Methods: Tumor biopsies were collected at baseline, on treatment,
and at disease progression (PD) (N =30; DLBCL n =19; FL n =9;
mantle cell lymphoma n =2), and from reference BNHL cases (N =
47 at diagnosis; N =39 R/R). Bcell markers were analyzed by semi
quantitative chromogenic CD20 immunohistochemistry (IHC) and
multiplex immunofluorescence. Tumorinfiltrating immune cells were
analyzed by multiplex immunofluorescence. Quantitative image
analysis was performed. Singlecell sequencing and flow cytometry
were performed in one patient with FL with PD 6 months post
therapy.
Results: Most baseline R/R BNHL biopsies (29/30, 96.7%) were
CD20+, whereas CD19 expression was variable. Relative baseline
IHC CD20 levels did not predict odronextamab response and CD20
intensity was similar in pts with FL or DLBCL. Moreover, 2/4 pts with
<100% CD20+B cells achieved durable responses. In 9/11 cases of
PD on treatment with paired biopsy samples available (DLBCL n =6;
FL n =3), loss of CD20 expression was observed; mutations ac-
counting for loss of CD20 expression were defined in three of these
pts (DLBCL n =2; FL n =1). These mutations were identified after
PD, where pts had received an active odronextamab dose and
experienced responses before progressing at weeks 24–25.
Baseline Tcell infiltration was higher in pts with FL vs DLBCL in
both the reference and study populations. Pts with DLBCL also had a
150
-
SUPPLEMENT ABSTRACTS
higher median density of Tcell infiltration in odronextamab re-
sponders vs nonresponders.
Singlecell analysis of a fresh lymph node sample from a case of
PD, occurring after a complete response to odronextamab, revealed a
nearcomplete loss of CD20 protein expression on B cells, while
maintaining CD19 and CD20 mRNA expression.
Conclusions: CD20 expression is almost ubiquitous in R/R BNHL
biopsy samples, whereas CD19 expression is variable. Durable
odronextamab responses were observed independently of variable
CD20 levels by IHC; therefore, baseline CD20 IHC expression is not
supported as a pt selection biomarker. Loss of CD20 cell surface
expression, caused by defined mutations leading to lack of protein
expression, occurred in several cases of relapsed disease, suggesting
targetdependent escape. We also observed an association between
Tcell infiltration at baseline and odronextamab response in DLBCL;
additional studies are ongoing.
The research was funded by: Regeneron Pharmaceuticals, Inc.
Keywords: Immunotherapy
Conflicts of interests pertinent to the abstract
J. BrouwerVisser
Employment or leadership position: Regeneron Pharmaceuticals, Inc
Stock ownership: Regeneron Pharmaceuticals, Inc
N. Fiaschi
Employment or leadership position: Regeneron Pharmaceuticals, Inc
Stock ownership: Regeneron Pharmaceuticals, Inc
R. P. Deering
Employment or leadership position: Regeneron Pharmaceuticals, Inc
Stock ownership: Regeneron Pharmaceuticals, Inc
A. Dhanik
Employment or leadership position: Regeneron Pharmaceuticals, Inc
Stock ownership: Regeneron Pharmaceuticals, Inc
K. J. Cygan
Employment or leadership position: Regeneron Pharmaceuticals, Inc
Stock ownership: Regeneron Pharmaceuticals, Inc
W. Zhang
Employment or leadership position: Regeneron Pharmaceuticals, Inc
Stock ownership: Regeneron Pharmaceuticals, Inc
S. Jeong
Employment or leadership position: Regeneron Pharmaceuticals, Inc
Stock ownership: Regeneron Pharmaceuticals, Inc
S. Pourpe
Employment or leadership position: Regeneron Pharmaceuticals, Inc
Stock ownership: Regeneron Pharmaceuticals, Inc
L. Boucher
Employment or leadership position: Regeneron Pharmaceuticals, Inc
Stock ownership: Regeneron Pharmaceuticals, Inc
S. Hamon
Employment or leadership position: Regeneron Pharmaceuticals, Inc
Stock ownership: Regeneron Pharmaceuticals, Inc
M. S. Topp
Consultant or advisory role: Amgen, KITE, Novartis, Regeneron, Roche
Research funding: Amgen, Boehringer Ingelheim, KITE, Regeneron,
Roche
R. Bannerji
Employment or leadership position: SanofiPasteur (Spouse)
Consultant or advisory role: AbbVie, Celgene, Regeneron
Research funding: AbbVie, Regeneron Pharmaceuticals, Roche
Genentech and Pharmacyclics LLC, an AbbVie Company
J. Duell
Research funding: Morphosys
R. H. Advani
Consultant or advisory role: Astra Zeneca, Bayer Healthcare Phar-
maceuticals, Cell Medica, Celgene, Genentech/Roche, Gilead, Kite-
Pharma, Kyowa, Portola Pharmaceuticals, Sanofi, Seattle Genetics,
Takeda
Other remuneration: INSTITUTIONAL RESEARCH SUPPORT: Cel-
gene, Forty Seven, Inc., Genentech/Roche, Janssen Pharmaceutical,
Kura, Merck, Millenium, Pharmacyclics, Regeneron, Seattle Genetics
D. M. Flink
Employment or leadership position: Regeneron Pharmaceuticals, Inc
Stock ownership: Regeneron Pharmaceuticals, Inc
A. Chaudhry
Employment or leadership position: Regeneron Pharmaceuticals, Inc
Stock ownership: Regeneron Pharmaceuticals, Inc
A. Sirulnik
Employment or leadership position: Regeneron Pharmaceuticals, Inc
Stock ownership: Regeneron Pharmaceuticals, Inc
I. Lowy
Employment or leadership position: Regeneron Pharmaceuticals, Inc
Stock ownership: Regeneron Pharmaceuticals, Inc
A. J. Murphy
Employment or leadership position: Regeneron Pharmaceuticals, Inc
Stock ownership: Regeneron Pharmaceuticals, Inc
D. M. Weinreich
Employment or leadership position: Regeneron Pharmaceuticals, Inc
Stock ownership: Regeneron Pharmaceuticals, Inc
G. D. Yancopoulos
Employment or leadership position: Regeneron Pharmaceuticals, Inc
Stock ownership: Regeneron Pharmaceuticals, Inc
G. Thurston
Employment or leadership position: Regeneron Pharmaceuticals, Inc
Stock ownership: Regeneron Pharmaceuticals, Inc
SUPPLEMENT ABSTRACTS
-
151
S. R. Ambati
Employment or leadership position: Regeneron Pharmaceuticals, Inc
Stock ownership: Regeneron Pharmaceuticals, Inc
V. Jankovic
Employment or leadership position: Regeneron Pharmaceuticals, Inc
Stock ownership: Regeneron Pharmaceuticals, Inc
095 |HIGHLY MULTIPLEX TISSUE IMAGING OF DLBCL
IDENTIFIES NOVEL PATHOLOGICAL FEATURES PREDICTIVE OF
OVERALL SURVIVAL
D. R. McNally
1
, H. Ravichandran
2
, W. Tam
3
, C. Steidl
4
, D. W. Scott
4
,
A. Melnick
5
, O. Elemento
2
1
Weill Cornell Medicine, Physiology and Biophysics, New York, New York,
USA,
2
Weill Cornell Medicine, Englander Institute for Precision Medicine,
New York, New York, USA,
3
Weill Cornell Medicine, Pathology and
Laboratory Medicine, New York, New York, USA,
4
BC Cancer, Centre for
Lymphoid Cancer, Vancouver, Canada,
5
Weill Cornell Medicine, Medicine,
New York, New York, USA
Introduction: Diffuse large Bcell lymphoma (DLBCL) is the most
common subtype of nonHodgkin lymphoma and is known to be a
highly heterogenous disease. Several recent studies have identified
subtypes based on prominent genetic patterns; however, efforts to
identify relationships between these genetic groups and the patho-
physiology of the disease remain limited. Characterization of tumor
phenotypes and their microenvironments alongside genomic alter-
ations will provide much needed context and may assist in identifying
novel therapeutic targets or improvements in patient stratification
without the use of genetic testing.
Methods: We used imaging mass cytometry (Hyperion imaging sys-
tem) to simultaneously quantify 2 sets of 37 target antigens across
serial sections of tumor tissues. A total of 64 unique antigens were
quantified across 1132 highdimensional images from 370 tumors.
Detailed clinical information including treatment outcome after R
CHOP immunotherapy is available for 303 patients, with informa-
tion on common genetic alterations available for 338. Existing
frameworks for cell segmentation (DeepCell) and singlecell clus-
tering (Seurat) were used to process and identify major cell types and
functional states in an unsupervised manner. Additionally, a propor-
tional hazards regression model incorporating normalized quantifi-
cation of all tumor biomarkers was used to identify relationships to
treatment outcome and survival.
Results: Clustering of patients solely by cellular composition resulted
in 8 distinct groups. Notably, a cluster depleted of tumor infiltrating
immune cells with high tumoral BCL2 expression was found to be
significantly enriched for MYC and BCL2 doublehit status (q =1.27
10
6
). In line with previous work, the doublehit associated cluster
had significantly worse overall survival (HR =2.45; p <0.0001).
Additionally, a subset defined by canonical ABC features, a high
proliferation score, and a prominent antiinflammatory immune
response was found to have poor OS (HR =1.45; p <0.05). As
previously reported, high CD20 expression was found to be signifi-
cantly associated with superior OS (HR =0.57; p <0.05). Tumor
expression of other markers including BCL2 (HR =1.3; p <0.05),
phosphohistone H3 s28 (HR =1.4; p <0.005), and Tbet (HR =1.4,
p<0.05) were found to be associated with inferior outcomes.
Conclusions: Advances in multiplex tissue imaging have provided a
framework to rapidly improve our understanding of tumor patho-
physiology and relationships with genomic alterations. Expanded
screening of antigen targets will likely yield novel biomarkers that
can then be translated to conventional IHC methods for improved
patient stratification.
The research was funded by: NIH grants UL1TR002384,
R01CA194547, LLSSCOR grants 18007802, 702120
Keywords: Bioinformatics; Computational and Systems Biology, Tu-
mor Biology and Heterogeneity, Aggressive Bcell nonHodgkin
lymphoma
Conflicts of interests pertinent to the abstract
A. Melnick
Consultant or advisory role: Epizyme, Constellation, KDAC Pharma,
BMS and ExoTherapeutics
Research funding: Janssen Pharmaceuticals, Sanofi and Daiichi Sankyo
O. Elemento
Consultant or advisory role: Freenome, Owkin, Volastra Therapeutics
and One Three Biotech
Research funding: Janssen, Johnson and Johnson, Volastra Thera-
peutics, AstraZeneca and Eli Lilly
096 |DIGITAL SPATIAL PROFILING OF DIFFUSE LARGE BCELL
LYMPHOMAS REVEALS STING AS AN IMMUNERELATED
DETERMINANT OF SURVIVAL AFTER RCHOP THERAPY
M. M. Hoppe
1
, S. Fan
2
, P. Jaynes
1
, Y. Peng
1
, X. Liu
3
, S. De Mel
3
, L.
Poon
3
, E. Chan
3
, J. Lee
3
, Y. L. Chee
3
, C. K. Ong
4
, T. Tang
5
, S. T. Lim
5
,
W. J. Chng
1
, N. F. Grigoropoulos
6
, A. VanSchoiack
7
, G. Bertolazzi
8
,
SiokB. Ng
1
, C. Tripodo
8
, A. D. Jeyasekharan
1
1
National University of Singapore, Cancer Science Institute of Singapore,
Singapore, Singapore,
2
National University of Singapore, Department of
Pathology, Yong Loo Lin School of Medicine, Singapore, Singapore,
3
National University Health System, Department of Haematology
Oncology, Singapore, Singapore,
4
National Cancer Centre Singapore, Di-
vision of Cellular and Molecular Research, Singapore, Singapore,
5
National
Cancer Centre Singapore, Division of Medical Oncology, Singapore,
Singapore,
6
Singapore General Hospital, Department of Haematology,
Singapore, Singapore,
7
NanoString Technologies Inc, Seattle, USA,
8
Uni-
versity of Palermo, Tumor Immunology Unit, Palermo, Italy
Background: Alterations in the immune infiltrate of Diffuse Large B
Cell Lymphoma (DLBCL) are known to influence survival. However,
the relative prognostic importance of different immune components
152
-
SUPPLEMENT ABSTRACTS
is not clear. Digital spatial profiling (DSP) enables highly multiplexed
proteinbased measurement of immune markers in a single tissue
section. Here, we applied DSP to evaluate the prognostic significance
of immune markers in RCHOP treated DLBCL.
Methods: We evaluated a custom NanoString immune panel in a
cohort of RCHOP treated DLBCL from the National University Hos-
pital Singapore (n=86) using DSP. Quantitative marker expression
values of 29 immune features were correlated with clinicopathological
features and with survival outcomes. Fluorescencebased quantitative
immunohistochemistry (fIHC) was applied to an independent DLBCL
cohort (MDA, n=36) to validate the prognostic relevance of STING.
We also analysed mRNA data sets from the following patient cohorts:
GSE117556 (RCHOP, n=469/RBCHOP, n=459), GSE10846 (R
CHOP, n=233/CHOP, n=181), GSE32918 (RCHOP, n=141),
GSE98588 (RCHOP, n=101) and GSE23501 (RCHOP, n=67).
Results: In a multivariate cox proportional hazards model analysing
DSP data, high levels of the monocytic/macrophagic marker CD163
were associated with poor progression free survival (PFS) and overall
survival (OS) (HR progression 3.8, p=0.008; HR death 5.4, p=0.010)
while high expression of the inflammatory mediator STING was
associated with better PFS and OS (HR progression 0.33, p=0.020;
HR death 0.17, p=0.007). Given the role of STING in mediating
immune activation after genotoxic chemotherapy, we further evalu-
ated the clinical relevance of pretreatment STING expression.
Quantitative fIHC of STING associated with improved survival in an
independent cohort (n =36, MDA). Furthermore, high expression of
STING (TMEM173) correlated with favourable prognosis across
multiple gene expression datasets: GSE117556, RCHOP, HR death
0.58, p=0.016; GSE117556, RBCHOP, HR death 0.34, p=0.0001;
GSE10846, CHOP, HR death 0.46, p<0.0001; GSE98588, RCHOP,
HR death 0.40, p=0.019. Consistently, DLBCL cell lines activated
immune signalling pathways when treated with chemotherapy in vi-
tro, which suggested that STING levels could positively affect prog-
nosis through inflammatory priming. In this setting, low STING
expression could be reminiscent of an immunologically cold dark
zone microenvironment imprint in DLBCL, being listed among genes
that we found transcriptionally induced in the darkzone to light
zone transition in reactive lymphoid follicles in situ.
Conclusions: High expression of STING confers good prognosis in
DLBCL, suggesting that STING signalling is important for chemo-
therapy induced immune clearance. STING agonists may thus have a
potential application alongside chemotherapeutic approaches in
DLBCL.
The research was funded by: SBN and ADJ are supported by the
Singapore Ministry of Health's National Medical Research Council
Transition Awards (CSAINV17nov016 and NMRC/TA/0020/2013 and
NMRC/TA/0052/2016). Work in ADJ's laboratory is funded by the
Cancer Science Institute of Singapore, National University of
Singapore through the National Research Foundation Singapore and
the Singapore Ministry of Education under its Research Centres of
Excellence initiative. This research is also supported by Singapore
Ministry of Health's National Medical Research Council under its
Singapore IYMPHoma translatiONal studY (SYMPHONY)
(OFLCG18May0028).
Keywords: Tumor Biology and Heterogeneity, Diagnostic and Prog-
nostic Biomarkers, Aggressive Bcell nonHodgkin lymphoma
Conflicts of interests pertinent to the abstract
A. VanSchoiack
Employment or leadership position: NanoString Technologies Inc
A. D. Jeyasekharan
Consultant or advisory role: Turbine Ltd, AstraZeneca, Janssen and
MSD
Research funding: Janssen and AstraZeneca
Educational grants: Perkin Elmer
097 |MYC, BCL2 AND BCL6 COEXPRESSION PATTERNS AT
SINGLECELL RESOLUTION REDEFINE DOUBLE EXPRESSOR
LYMPHOMAS
M. M. Hoppe
1
, P. Jaynes
1
, S. Fan
2
, Y. Peng
1
, P. M. Hoang
1
, X. Liu
3
, S.
De Mel
3
, L. Poon
3
, E. Chan
3
, J. Lee
3
, Y. L. Chee
3
, C. K. Ong
4
, T. Tang
5
,
S. T. Lim
5
, N. F. Grigoropoulos
6
, S.Y. Tan
2
, S. S.S. Hue
2
, S.T. Chang
7
,
S.S. Chuang
7
, S. Li
8
, J. D. Khoury
8
, H. Choi
9
, P. Farinha
10
, A.
Mottok
11
, D. W. Scott
10
, WeeJ. Chng
1
, S.B. Ng
1
, C. Tripodo
12
, A. D.
Jeyasekharan
1
1
National University of Singapore, Cancer Science Institute of Singapore,
Singapore, Singapore,
2
National University of Singapore, Department
of Pathology, Yong Loo Lin School of Medicine, Singapore, Singapore,
3
National University Health System, Department of Haematology
Oncology, Singapore, Singapore,
4
National Cancer Centre Singapore,
Division of Cellular and Molecular Research, Singapore, Singapore,
5
National Cancer Centre Singapore, Division of Medical Oncology,
Singapore , Singapore,
6
Singapore General Hospital, Department of
Haematology, Singapore , Singapore,
7
ChiMei Medical Center, Depart-
ment of Pathology, Tainan, Taiwan,
8
The University of Texas MD
Anderson Cancer Center, Department of Hematopathology, Division
of Pathology and Laboratory Medicine, Houston, USA,
9
National
University of Singapore, Department of Medicine, Yong Loo Lin School of
Medicine, Singapore, Singapore,
10
BC Cancer Research Centre, Depart-
ment of Lymphoid Cancer Research, Vancouver, Canada,
11
University
Medical Center and University of Ulm, Institute of Human Genetics,
Ulm, Germany,
12
University of Palermo, Tumor Immunology Unit,
Palermo, Italy
Introduction: ‘Double Expressor Lymphomas’ (DEL) refer to Diffuse
Large BCell Lymphomas (DLBCL) which are positive for MYC and
BCL2 by immunohistochemistry (IHC); and have poorer outcomes on
standard RCHOP therapy. BCL6 expression in these tumors partly
negates this prognostic effect. However, in routine IHC, these on-
cogenes are evaluated independently without probing their co
expression at the singlecell level. It is therefore not known if DELs
are tumours that contain distinct MYC, BCL2 and/or BCL6
SUPPLEMENT ABSTRACTS
-
153
expressing clones, or if there are patterns of coexpression under-
lying their prognostic signficance.
Methods: We used multiplexed fluorescencebased quantitative
IHC (qIHC) to study oncogene coexpression at singlecell resolution
in four independent DLBCL cohorts: NUH (n=152), CMMC (n=
150), SGH (n=67), MDA (n=40). Mathematically modelled analyses
were performed to validate findings in gene expression cohorts
GSE10846(n =420), GSE31312(n =498), GSE32918 (n =140),
GSE117556(n =928) and a cohort with curated IHC scores; BCC (n =
316).
Results: In nonmalignant lymphoid tissues we observed spatially
ordered patterns of MYC, BCL2 and BCL6 coexpression, charac-
terised by mutually exclusive patterns of BCL2 and BCL6 expression
in the nongerminal centre and germinal centre compartments
respectively. In contrast, we noted grossly disordered patterns of
MYC(M), BCL2(2), and BCL6(6) coexpression in DLBCL. Tumors
showed unique repertoires of cells displaying eight possible permu-
tations of coexpression: M+2+6+, M+2+6, M+26+, M+26, M2
+6+, M26+, M2+6and M26, highlighting a novel aspect of
DLBCL heterogeneity. Among these, the extent of the M+2+6sub
population robustly identified unfavourable DLBCL cases across 3
independent cohorts, offering a new definition of DEL. Interestingly,
the extent of the M+2+6subpopulation could be accurately pre-
dicted from individual M, 2, 6 expression data using a mathematical
model, with the predicted extent correlating well with actual coloc-
alization by qIHC. By applying this model to datasets where only
individual expression data was available (gene expression datasets
and a cohort of conventional visuallyscored IHC), we were able to
validate a robust association of the extent of the M+2+6subpop-
ulation with poor survival. Importantly, cases with high M+2+6
subpopulations were enriched in the newly described MCD and A53
genetic subgroups of DLBCL, consistent with their poorer outcomes.
Conclusions: By investigating singlecell resolved MYC, BCL2 and
BCL6 coexpression in DLBCL we have identified a subpopulation
that robustly predicts prognosis and can refine the traditional defi-
nition of DEL. The mathematical model for estimating subclonal co
expression from individual oncogene expression data may be appli-
cable to studies of prognostic markers in multiple cancer types.
The research was funded by: ADJ was supported by the Singapore
Ministry of Health's National Medical Research Council Transition
Award (NMRC/TA/0052/2016). Work in ADJ's laboratory is funded
by a core grant from the Cancer Science Institute of Singapore, Na-
tional University of Singapore through the National Research Foun-
dation Singapore and the Singapore Ministry of Education under its
Research Centres of Excellence initiative, as well as by Singapore
Ministry of Health's National Medical Research Council 'Singapore
lYMPHoma translatiONal studY (SYMPHONY)' Open Fund Large
Collaborative Grant (MOH00020503).
Keywords: Tumor Biology and Heterogeneity, Aggressive Bcell non
Hodgkin lymphoma, Pathology and Classification of Lymphomas
Conflicts of interests:pertinent to the abstract
A. D. Jeyasekharan
Consultant or advisory role: Turbine Ltd, AstraZeneca, Janssen and
MSD
Research funding: Janssen and AstraZeneca
Educational grants: Perkin Elmer
098 |NANOSTRING ANALYSIS OF MYCOSIS FUNGOIDES
OFFERS CLUES TO BETTER UNDERSTAND MF PATHOGENESIS
AND PROGRESSION
R. AlonsoAlonso
1
, M. Rodriguez
1
, N. GarcíaDíaz
2
, J. P. Vaqué
2
,
L. TomásRoca
3
, L. Cereceda
1
, S. M. RodriguezPinilla
1
, R. Córdoba
4
,
J. F. García
5
, J. L. RodriguezPeralto
6
, P. Ortiz Romero
7
, M. Án. Piris
Pinilla
1
1
Instituto de Investigación Sanitaria Fundación Jiménez Díaz. CIBERONC,
Pathology, Madrid, Spain,
2
Universidad de Cantabria.Infección,
Inmunidad & Patología Digestiva, Instituto de Investigación Marqués de
ValdecillaIDIVAL , Molecular Biology, Santander, Spain,
3
Instituto de
Investigación Sanitaria Fundación Jiménez Díaz, Pathology, Madrid, Spain,
4
Hospital Universitario Fundación Jiménez Díaz. CIBERONC, Haematology,
Madrid, Spain,
5
Hospital MD Anderson Cancer Center.CIBERONC, Pa-
thology, Madrid, Spain,
6
Hospital MD Anderson Cancer Center, Pahology,
Madrid, Spain,
7
Universitario 12 de Octubre, I+12 Research Institute,
Universidad Complutense. CIBERONC, Dermatology, Madrid, Spain
Introduction: Mycosis fungoides (MF) and Sézary syndrome (SS) are
the most common subtypes of cutaneous Tcell lymphomas. The
diagnosis of these patients is very challenging and requires an inte-
grated approach, incorporating clinical, morphological, immunophe-
notypic and molecular features. The molecular substrate of early and
advanced stages of MF / SS is still poorly understood and, consequently,
treatment selection is mainly based on clinical data. The study aimed to
transfer what is known about the molecular pathogenesis of MF / SS to
early diagnosis, prognosis, and selection of therapy by identifying
molecular markers associated with the course of the disease.
Methods: Using the NanoString platform for geneexpression anal-
ysis, we design a custom panel of 77 genes relevant in the patho-
genesis of MF/SS, together with genes known to be therapeutic
targets. A series of 81 formalinfixed, paraffinembedded (FFPE)
samples belonging to 27 MF/SS patients in different phases of the
disease are included in the study.
Results: The technique was informative in all analyzed cases, inde-
pendently of the clinical or histological stage or density of the tumor
infiltration. For each case or sample the analysis provided an objec-
tive measure of the Tcell phenotype (Tcell differentiation gene
sets), cellular composition of the infiltrate (dendritic cells, macro-
phages, Bcells,…) expression of markers used for therapy selection
(CD30,CXCR4 and KIR3DL2) and expression level of surrogate
markers for the main cellsurvival oncogenic pathways.
Unexpectedly, nonsupervised clustering showed that most of
the clustering was dependent of the patient identity, suggesting that
154
-
SUPPLEMENT ABSTRACTS
MF/SS has a high degree of intertumoral heterogeneity and that
molecular signature for each patient tends to remain relatively stable
along the disease.
Samples corresponding to preMF lesions tend to cluster with
early MF/SS samples, suggesting that preMF lesions indeed corre-
spond to early phases of the disease.
On the other hand, patients who progress to advanced stages
have a tendency to cluster with each other. Several differentially
expressed genes were comparing early and advanced stages. FGFR3,
NUAK1, FJX1, CXCL12 and RORC were up regulated in early lesions,
while CARD11, CD2, CD38, CD3D, CD3E, CD3G, CXCR4, GZMA, IL10
and SELL were up regulated in tumors (p <0,005).
Conclusions: Geneexpression profiling using a customized Nano-
String platform can be applied to routine paraffin embedded MF/SS
samples and provides data that allow to a better understanding of
MF genesis and progression. MF/SS samples show an unexpected
high degree of intertumoral heterogeneity, suggesting that every
patient has some individual molecular signature features that are
found in consecutive biopsies.
The analysis brings also particular gene signatures associated
with early MF and progression, allowing recognizing stagespecific
signatures.
EA previously submitted to regional or national meetings (up to
1000 attendees)
The research was funded by: The research was supported by grants
from Instituto de Salud Carlos III, from Ministerio de Economía,
Industria y Competitividad, Asociación Española Contra el Cáncer
(AECC), Comunidad Autónoma de Madrid and Centro de Inves-
tigación Biomédica en Red de Cáncer (CIBERONC): SAF2013
47416R, CIBERONCISCIII, ISCIIIMINECOAESFEDER (Plan
Estatal I +D+I 20132016), AECC PROYE18054PIRI, CAM B2017/
BMD3778, PIC97/2017_FJD, PIE15/0081, PIE16/01294 and PIE19/
00715.
L.TomasRoca was funded by Marie SkłodowskaCurie Individual
Fellowship (No 882597)
Keywords: Genomics, Epigenomics, and Other Omics, Diagnostic
and Prognostic Biomarkers, Cutaneous nonHodgkin lymphoma
Conflicts of interests pertinent to the abstract
M. Án. Piris Pinilla
Consultant or advisory role: Millenium/Takeda. Celgene. Gilead.
Jansen. Nanostring. Kyowa Kirin
Research funding: Millenium/Takeda. Gilead. Kura
099 |9P GAIN PREDICTS OUTCOMES IN PATIENTS WITH
RELAPSED/REFRACTORY (R/R) DIFFUSE LARGE BCELL
LYMPHOMA (DLBCL) TREATED WITH RGEMOX +/
ATEZOLIZUMAB. ARGO: A RANDOMISED PHASE II STUDY
A. Davies
1
, P. McKay
2
, W. Osborne
3
, L. Stanton
1
, O. TansleyHancock
1
,
M. Lawrence
1
, K. Mercer
1
, A. Allen
1
, B. Pottinger
4
, A. Zhelyazkova
5
,
F. Miall
6
, J. Rafferty
7
, B. Sale
1
, F. Cucco
8
, L. Nunn
1
, A. Coleman
1
,
G. Griffiths
1
, M. Q. Du
8
, C. Burton
9
, S. Barrons
9
, P. Johnson
1
1
University of Southampton, Southampton Cancer Research UK (CRUK)
Centre, CRUK/NIHR Experimental Cancer Medicines Centre, CRUK
Southampton Clinical Trials Unit, Southampton, UK,
2
Beatson West of
Scotland Cancer Centre, Department of Haematology, Glasgow, UK,
3
Freeman Hospital, The Newcastle upon Tyne Hospitals NHS Foundation
Trust, Department of Haematology, Newcastle, UK,
4
Royal Cornwall
Hospitals NHS Trust, Department of Haematology, Truro, UK,
5
The
Pennine Acute Hospitals NHS Trust, Department of Haematology,
Manchester, UK,
6
University Hospitals of Leicester NHS Trust,
Department of Haematology, Leicester, UK,
7
Patient Representative, c/o
CRUK Southampton Clinical Trials Unit, Southampton, UK,
8
University of
Cambridge, Department of Pathology, Cambridge, UK,
9
Leeds Cancer
Centre, Haematological Malignancies Diagnostic Service, Leeds, UK
Introduction: Outcomes for transplant ineligible R/R DLBCL pts are
poor. Atezolizumab (A), a humanised anti PDL1 with limited single
agent activity in DLBCL, may provide a novel mechanism to improve
outcomes from rituximab (R), gemcitabine (Gem) and oxaliplatin (Ox)
(RGemOx) immunochemotherapy. Chemotherapy may reduce reg-
ulatory Tcell activity, enhance crosspresentation of tumour anti-
gens and induce PDL1 expression. This leads to synergistic clinical
activity in some solid tumours.
Methods: ARGO was an openlabel randomised phase II trial with a
3:1 randomisation favouring the experimental arm (Arm B) with no
formal planned direct arm comparison. Stratification was by R/R sta-
tus. RGemOx was delivered for 6 cycles on a 14day schedule: R cycle
1 IV 375mg/m
2
, cycle 26 sc 1400mg; Gem 1000mg/m
2
; Ox 100mg/m
2
with GCSF support (Arm A). In Arm B A 840mg IV was added every 14
days from cycle 2 onwards, responding pts continued with A at 840mg
every 21 days for 8 cycles. The primary endpoint was 1year pro-
gression free survival (PFS), aiming for 40%, to exclude a rate <25%.
The study planned to recruit 112 pts but stopped early on the
recommendation of the Data Monitoring Committee due to failure to
reach the prespecified futility boundary.
Results: Between July 2018 and June 2020, 53 transplant ineligible
DLBCL pts were enrolled (Arm A n =12 Arm B n =41). The median
age was 73 years (2385), median previous lines of therapy was 1 (1
7). 74% had IPI 3 at entry, 58% refractory, 42% relapsed. Three pts
were double hit, 21 double expressors and 16 ABC. TP53 was
mutated in 44%. 72% of pts completed 6 cycles of induction therapy,
10 withdrawals due to progressive disease (PD), 4 subject/investi-
gator withdrawals, 1 death (pneumonia). The overall response rate
(ORR) was 38% (CR 13%) in Arm B and 27% (CR 9%) in Arm A. Of 16
pts that started maintenance, 63% (10 pts) prematurely stopped (5
PD, 4 trial cessation and 1 proceeded to highdose therapy). PFS at
12 months was 15.2% (95%CI 5.828.8) in Arm B and 8.3% (95%CI
0.5131.1) with RGemOx alone. Overall survival at 12 months:
53.9% (95%CI 37.068.1) Arm B, 58.3% (95%CI 27.080.1) Arm A.
Grade 3 toxicity in 10% patients was thrombocytopenia (Arm A
25% Arm B 32%) and neutropenia, pneumonia and pyrexia (Arm A
0% Arm B 10% each). In Arm B, ORR, PFS and OS were higher in
SUPPLEMENT ABSTRACTS
-
155
tumours with gain of PDL1 locus at 9p by FISH (10/29), median PFS
7.2 months 9p gain vs 3.2 months normal P =0.037, median OS not
reached in gain 9p vs 5 months P =0.025. This was not reflected in
protein expression by immunohistochemistry. There was no differ-
ence in outcome by peripheral blood immune effector cell numbers,
double expressor status or cell of origin.
Conclusions: The efficacy of RGemOx was disappointing and not
improved by the addition of A. Further evaluation in pts with PDL1
gain at 9p is warranted. Funding support from Roche, endorsed by
CRUK (CRUKE/16/028). A UK National Cancer Research Institute
Lymphoma Group study.
The research was funded by: F. HoffmannLa Roche
Keywords: Aggressive Bcell nonHodgkin lymphoma, Combination
Therapies
Conflicts of interests pertinent to the abstract
A. Davies
Consultant or advisory role: Celgene, Roche, Gilead/Kite Pharma,
Takeda, Kayropharma, Incyte, VelosBio
Honoraria: Celgene, Roche, Gilead/Kite Pharma, Takeda, Janssen,
Acerta Pharma, AstraZeneca, ADC Therapeutics, Incyte, VelosBio
Research funding: Celgene, Roche, Gilead/Kite Pharma, Takeda, Jans-
sen, Kayropharma, Acerta Pharma, AstraZeneca, ADC Therapeutics
Educational grants: Celgene, Roche
P. McKay
Consultant or advisory role: TAKEDA, Roche, Celgene, Kite and
Beigene
Honoraria: TAKEDA, Roche, Celgene, Kite and Beigene
W. Osborne
Consultant or advisory role: Roche, Takeda, Servier, Kite Gilead,
MSD, Novartis, Beigene, Syneos, Autolus
Honoraria: Pfizer, Astra Zeneca, Roche, Takeda, Kite Gilead, Novartis,
Kyowa Kirin
Educational grants: Novartis, Takeda, Pfizer, Roche
F. Miall
Consultant or advisory role: Roche and Takeda
Honoraria: Roche and Takeda
G. Griffiths
Research funding: JannsennCilag, AZ, Novartis, Astex, Roche,
Heartflow, BMS, BionTech
Other remuneration: Celldex
C. Burton
Consultant or advisory role: Roche
P. Johnson
Consultant or advisory role: Epizyme, Janssen, Oncimmune, Boeh-
ringer Ingelheim
Honoraria: Bristol Myers Squibb, Celgene, Genmab, Incyte, Kite
Pharma, Kymera, MorphoSys, Novartis, Takeda
Research funding: Epizyme
100 |MOLECULAR HIGH GRADE (MHG) GENE EXPRESSION
PROFILE IN DLBCL IS ENRICHED AMONG PATIENTS WITH EARLY
TREATMENT FAILURE
S. L. Barrans
1
, F. Cucco
2
, J. Davies
3
, M. van Hoppe
1
, T. Mell
1
, K.
Mercer
4
, l. Stanton
4
, J. Caddy
4
, R. Tooze
5
, C. Burton
1
, D. Westhead
3
,
M. Du
2
, A. Davies
4
, P. Johnson
6
1
Leeds Teaching Hospitals, HMDS, Institute of Oncology, Leeds, UK,
2
University of Cambridge, Department of Pathology, Cambridge, UK,
3
University of Leeds, Bioinformatics Group, Faculty of Biological sciences,
Leeds, UK,
4
University of Southampton, SCTU, Southampton, UK,
5
University or Leeds, School of medicine, Leeds, UK,
6
University of
Southampton, Medicine, Southampton, UK
Diffuse large B cell lymphoma (DLBCL) is biologically and clinically
heterogenous, with variable response to standard treatment. We
previously described a subgroup of DLBCL with a GCBlike gene
expression signature similar to that of Burkitt lymphoma and
156
-
SUPPLEMENT ABSTRACTS
enriched for ‘double hit’ FISH status. This molecular high grade
(MHG) subset of patients was identified from the REMoDLB trial
using Illumina WGDASL data and showed an inferior response to R
CHOP,
1
confirmed in our population based cohort.
2
The MaPLe trial (Molecular Profiling for Lymphoma) is a multi-
centre prospective observational cohort study for the collection of
tumour samples from patients with DLBCL, with almost 3000 sam-
ples now collated.
The aim of this analysis was to characterise lymphomas that
progressed early according to gene expression profiling (GEP) status,
including MHG and cell of origin (COO), as well as double hit FISH
status and targeted sequencing.
Patients who progressed within 6 months of MaPLe study baseline
visit were identified. To allow assessment of biological variables which
may contribute to treatment failure, each case was matched to another
patient who had not progressed within 6 months based on age and IPI
score at diagnosis. Samples with sufficient material were interrogated
using the HTG EdgeSeq Pan BCell Lymphoma Panel and classified
according to MHG and COO status. Targeted sequencing of 191 gene/
region targets using TWIST library prep, sequenced on an Illumina
HiSeq was also performed and FISH for double hit status is underway.
Thirty nine eligible patients were identified as ‘early progressors’
and matched to 39 controls. HTG data was available and passed QC
metrics in 64 patients (32 from each group). In total, 18/64 (28%)
were classified as MHG, with 12/18 of these (67%) represented
within the early progressor group. This is significantly higher than the
prevelance of MHG previously demonstrated in REMoDLB and
population based datasets, reflecting the case selection within this
study. ABCs were evenly distributed between groups (11/21 vs 10/
21) while GCBs and unclassifiable samples were slightly more prev-
alent in the control group (7/18 vs 11/18 and 2/7 vs 5/7 respec-
tively). Relevant mutations, previously described to be associated
with ABC, GCB and MHG, were demonstrated within the GEP sub-
groups, however there was no significant association between indi-
vidual or subtypespecific mutations and progression.
The results of this study confirm that the MHG gene expression
profile can be reproduced using HTG EdgeSeq Pan BCell Lymphoma
Panel data. MHG was more frequently identified in the early pro-
gressor cohort, suggesting that MHG GEP contributes to poor
response to conventional RCHOP treatment for DLBCL. Prospective
identification of this group for testing more effective treatment
strategies is a priority.
1. Sha et al. J Clin Oncol. 2019;37(3):202212
2. Painter et al. BJH 2019;185(4):781784
The research was funded by: Bloodwise (Blood Cancer UK)
Keywords: Diagnostic and Prognostic Biomarkers, Aggressive Bcell
nonHodgkin lymphoma, Pathology and Classification of Lymphomas
Conflicts of interests pertinent to the abstract
P. Johnson
Consultant or advisory role: Takeda, BristolMyers Squibb, Novartis,
Genmab, InCyte, Morphosys, Kymera
Research funding: Janssen, Epizyme
101 |CHARACTERIZATION OF THE GENETIC LANDSCAPE OF
HIGHGRADE BCELL LYMPHOMA, NOS AN LLMPP PROJECT
B. J. Collinge
1
, L. K Hilton
1
, J. Wong
1
, S. BenNeriah
1
, C. K. Rushton
2
,
G. W. Slack
1
, P. Farinha
1
, J. R. Cook
3
, G. Ott
4
, A. Rosenwald
5
, E.
Campo
6
, C. Amador
7
, T. C. Greiner
7
, P. W. Raess
8
, J. Y. Song
9
, G.
Inghirami
10
, E. S. Jaffe
11
, D. D. Weisenburger
9
, W. C. Chan
9
, H.
Holte
12
, K. Beiske
13
, K. Fu
14
, J. Delabie
15
, S. Pittaluga
11
, A. L. Feld-
man
16
, K. J. Savage
1
, A. J. Mungall
17
, L. M. Staudt
18
, C. Steidl
1
, L. M.
Rimsza
19
, R. D. Morin
2
, D. W. Scott
1
1
BC Cancer, Centre for Lymphoid Cancer, Vancouver, Canada,
2
Simon Fraser University, Molecular Biology and Biochemistry,
Burnaby, Canada,
3
Cleveland Clinic, Department of Molecular Pathology
and Laboratory Medicine, Cleveland, Ohio, USA,
4
RobertBosch
Krankenhaus and Dr. Margarete FischerBosch Institute of Clinical Phar-
macology, Department of Clinical Pathology, Stuttgart, Germany,
5
Uni-
versity of Wuerzburg, Institute of Pathology, Wuerzburg,
Germany,
6
Hospital Clinic of the University of Barcelona, Department of
Pathology, Barcelona, Spain,
7
University of Nebraska Medical Center,
Department of Pathology and Microbiology, Omaha, Nebraska, USA,
8
Oregon Health & Science University, Department of Pathology, Portland,
Oregon, USA,
9
City of Hope National Medical Center, Department of Pa-
thology, Duarte, California, USA,
10
Weill Cornell Medicine, Pathology and
Laboratory Medicine, New York, New York, USA,
11
National Cancer Insti-
tute, Laboratory of Pathology, Bethesda, Maryland, USA,
12
Oslo University
Hospital, Department of Oncology, Oslo, Norway,
13
Oslo University Hos-
pital, Department of Pathology, Oslo, Norway,
14
Roswell Park Cancer
Institute, Department of Pathology & Laboratory Medicine, Buffalo, New
York, USA,
15
University Health Network and University of Toronto,
Department of Laboratory Medicine and Pathobiology, Toronto, Canada,
16
Mayo Clinic College of Medicine, Laboratory Medicine and Pathology,
Rochester, Minnesota, USA,
17
BC Cancer, Canada's Michael Smith Genome
Sciences Centre, Vancouver, Canada,
18
National Cancer Institute, Center
for Cancer Research, Bethesda, Maryland, USA,
19
Mayo Clinic, Department
of Laboratory Medicine and Pathology, Scottsdale, Arizona, USA
Introduction: Highgrade Bcell lymphoma encompasses (1) tumours
with MYC and BCL2 and/or BCL6 rearrangement (HGBLDH/TH),
and (2) tumours lacking this combination of rearrangements but
displaying “highgrade” morphology (HGBLNOS) blastoid or
morphology intermediate between diffuse large Bcell lymphoma
(DLBCL) and Burkitt lymphoma (BL). Limited by the rarity of HGBL
NOS, it remains unclear whether these tumours share a unifying
biology and/or bear molecular similarity to HGBLDH/TH. This un-
certainty is further confounded by interobserver variability in
morphological assessment and artifacts introduced during tissue
fixation. Here, we aim to characterize the molecular features of
HGBLNOS, as confirmed by central pathology review (CPR) by a
panel of expert lymphoma pathologists, to determine if it represents
a biologically distinct subset of tumours.
Methods: Archival diagnostic tissue biopsies from 93 HGBLNOS
tumours were submitted from LLMPP sites, with fluorescent in situ
hybridization (FISH) testing for MYC,BCL2 and BCL6 to exclude
SUPPLEMENT ABSTRACTS
-
157
HGBLDH/TH. CPR has been completed for 61 tumours. Cellof
origin (COO) and double hit signature (DHITsig) were determined
by gene expression profiling. Recurrent somatic mutations (SNVs/
Indels) were identified from the intersection of three out of four
predictions by Strelka2, LoFreq, Mutect2 and SAGE on whole
genome or exome sequencing of 46 tumours. Genetic subtypes were
assigned using the LymphGen data portal.
Results:MYC rearrangement was detected in approximately half of all
identified tumours, while a similar but not fully overlapping proportion
were DHITsig+. Cases spanned the GCB (56%) and ABC (28%) COO
subgroups, with 16% unclassified. Following CPR, nearly half of tu-
mours were reclassified as DLBCL (44%) or BL (5%). The frequency of
MYC rearrangement and the distribution of COO subgroups was
similar between tumours confirmed as HGBLNOS and those reclas-
sified as DLBCL, while 55% of confirmed HGBLNOS were DHITsig+
compared with 39% of reassigned tumours. Few recurrently mutated
genes were shared among confirmed HGBLNOS tumours and no
differentially mutated genes were identified through comparison to
tumours reclassified as DLBCL. While most tumours were unclassified
by the LymphGen algorithm, the remainder were spread across EZB
(13%), MCD (9%), ST2 (7%), and BN2 (4%).
Conclusion: The high reclassification rate highlights the difficulty in
distinguishing highgrade morphology, while the lack of shared mo-
lecular features among CPR confirmed HGBLNOS suggests this
morphological distinction identifies a heterogeneous group of tu-
mours. Furthermore, these tumours appear to be largely unrelated to
HGBLDH/THBCL2, which are almost all uniformly EZB, GCB and
DHITsig+. Further molecular characterization and comparisons to
related entities is required to determine how these tumours are best
classified.
158
-
SUPPLEMENT ABSTRACTS
Keywords: Genomics, Epigenomics, and Other Omics, Aggressive B
cell nonHodgkin lymphoma, Pathology and Classification of
Lymphomas
No conflicts of interest pertinent to the abstract.
102 |RNA SEQUENCING REVEALS DIFFERENT GENE
EXPRESSION IN MALE VERSUS FEMALE DIFFUSE LARGE BCELL
LYMPHOMA
P. Ghione
1
, E. Cortes Gomez
2
, P. Torka
1
, S. Sundaram
1
, C. Mavis
1
, F.
Tabbo'
3
, J. Gu
1
, M. T. Cacciapuoti
4
, L. Yoffe
5
, J. Wang
2
, F. Hernandez
Ilizaliturri
1
, G. Inghirami
4
1
Roswell Park Comprehensive Cancer Center, Lymphoma, Buffalo, NY,
USA,
2
Roswell Park Comprehensive Cancer Center, Biostatistics, Buffalo,
New York, USA,
3
Universita' degli Studi di Torino, Oncology, Torino, Italy,
4
Weill Cornell Medicine, Hematopathology, New York, USA,
5
Weill Cornell
Medicine, Biostatistics, New York, New York, USA
Introduction: Male gender is known to represent a risk factor for
survival, in several lymphoma subtypes (Lim, Loy et al. 2015, Nabhan,
Zhou et al. 2016). This is well established in Hodgkin's(Hasenclever and
Diehl 1998) and follicular lymphoma (Federico, Vitolo et al. 2000, Solal
Céligny, Roy et al. 2004), where male (M) gender has been included as a
prognostic factor in some of the prognostic indices. Moreover, large
cohorts of diffuse large B cell lymphoma (DLBCL) show that female (F)
experience longer progressionfree survival (Junlén, Lockmer et al.
2020), with significant differences between genders in pts >60 years
old in the rituximab era(2014). Recent data have also demonstrated
that F with DLBCL have superior responses and longer duration to
antiCD19 CART cell therapy than M counterparts (Nastoupil, Jain
et al. 2020). The biological phenomena behind these clinical differences
remain unknown. We hypothesized that differences in gene expression
in M and F might explain patients’ outcomes in F DLBCL.
Methods: We analyzed total RNA sequencing (RNAs) data as previ-
ously described (Treater M, Nat Commun 2018) from frontline naïve
DLBCL treated with RCHOPlike regimens, enriched for relapsed/
refractory cases (n =23 r/r, 32 sensitive). DESeq2 (v1.30.1) was used
with a 2 2 factor design involving gender and treatment response (r/r
vs nonr/r) to identify differentially expressed genes. A gene with FC >
1.5 and FDR <0.05 was considered as statistically significant. The
obtained gene lists were further refined by removing genes known to
be preferentially expressed in M or F. The list was tested for pathway
enrichment analysis against MSigDB's Hallmark and C2CP databases
using Fisher's exact test. Significant pathways are chosen after multiple
test adjustment with cutoff value of FDR <0.05.
Results: Among 55 naïve DLBCL cases, 23 were F (11 r/r, 12 nonr/
r), 34 M (12 r/r, 20 nonr/r). The top 50 genes upregulated or
downregulated in F were stratified and sorted in columns grouping
r/r and nonr/r cases for each gender. Genes such as SMC1B,
TCL1B, MSTN were upregulated in F, while BCORP1, CCNA1, AK5
were upregulated in M. Pathways evaluation showed that TGFbeta,
TP53 and IL6JAK/STAT3 were upregulated specifically in r/r F,
whereas MYC, E2F, PI3K/AKT/MTOR were selectively upregulated
in nonr/r F cases. Intriguingly, both these sets of pathways were
downregulated in M cases. Further analysis is ongoing and will be
presented.
Conclusions: We demonstrate that F and M DLBCL have differential
gene expression profiling and putative activation of selected path-
ways. Further exploration and validation of these differences in
larger cohorts can lead to a better understanding of the therapeutic
variability noted between the two genders.
Keywords: Pathology and Classification of Lymphomas
No conflicts of interest pertinent to the abstract.
103 |TESTICULAR DIFFUSE LARGE BCELL LYMPHOMA:
CLINICOBIOLOGICAL CHARACTERIZATION, EVALUATION OF
TREATMENT RESPONSE AND SURVIVAL
A. RivasDelgado
1
, C. López
2
, F. Nadeu
2
, M. Grau
2
, A. Rivero
1
, J.
Bosch
3
, M. Alcoceba
4
, T. Gustavo
5
, L. Luizaga
6
, C. Barcena
7
, N. Kel-
leher
8
, S. Martin
2
, P. Mozas
1
, O. Balague
1
, G. Frigola
1
, L. Magnano
1
, T.
Baumann
7
, N. Villamor
1
, A. Muntañola
6
, J. M. Sancho
5
, A. Martin
GarcíaSancho
4
, E. GonzalezBarca
9
, F. Climent
3
, E. Campo
2
, E. Giné
1
,
A. LópezGuillermo
1
, S. Beà
2
1
Hospital Clínic de Barcelona, Hematology and Pathology Departments,
Barcelona, Spain,
2
Instituto de Investigaciones Biomédicas August Pi i
Sunyer (IDIBAPS), Molecular pathology of lymphoid neoplasms, Barcelona,
Spain,
3
Hospital de Bellvitge, IDIBELL, Pathology Department, Barcelona,
Spain,
4
Hospital Universitario de Salamanca, Hematology Department,
Salamanca, Spain,
5
ICOIJCHospital Universitari Germans Trias i
Pujol, Hematology and Pathology Departments, Badalona, Spain,
6
Hospital
Universitari Mutua de Terrassa, Hematology and Pathology Departments,
Terrasa, Spain,
7
Hospital Universitario 12 de Octubre, Hematology
and Pathology Departments, Madrid, Spain,
8
Institut Català d'Oncologia
Hospital de Palamos, Hematology Department, Girona, Spain,
9
Institut
Català d’OncologiaHospital Duran i Reynals, IDIBELL, Universitat de
Barcelona, Hematology Department, L'Hospitalet de Llobregat, Spain
Background: Testicular diffuse large Bcell lymphoma (TDLBCL) is
an infrequent and aggressive lymphoma accounting for 12% of all
nonHodgkin's lymphomas. Although prognosis improved with the
introduction of rituximab, the outcome of these patients is still poor.
This study aimed to analyze the clinical features and outcome of a
series of TDLBCL as well as to characterize their genomic profile.
Methods: We collected 62 patients with TDLBCL diagnosed be-
tween 2002 and 2020. DNA was extracted from formalinfixed
paraffinembedded (FFPE) tissue biopsies. Copy number alterations
(CNA) were studied using OncoScanTM CNV FFPE arrays (Thermo-
fisher) (n =17) and gene mutations by a Bcell malignancyoriented
targeted nextgeneration sequencing (NGS) panel containing 121
genes (SureSelectXT, Agilent Technologies) (n =15). The genomic
status of BCL2,BCL6,MYC, and JAK2 locus was also investigated by
FISH in 33 cases.
SUPPLEMENT ABSTRACTS
-
159
Results: Median age at diagnosis was 69 (3089) years. Sixtyseven
percent of the cases had stages I/II, 72% lowor lowintermediate
risk IPI, and 84% (32/39) showed a nongerminal center phenotype
(Hans algorithm). In 15 patients with available NGS, the most
frequently mutated genes were MYD88
L265P
(67%), PIM1 (60%),
KMT2D (60%), CD79B (40%), CREBBP (33%), and TBL1XR1 (47%)
(Figure 1A). Of note, none of the patients with localized stages had
CIITA mutations (p =0.011). MYC,BCL2, and BCL6 rearrangements
were observed in 0%, 9%, and 31% of cases by FISH, respectively. We
detected CNA in all samples with a median of 13 alterations per case
(range, 133), including a median of 6 gains (125), 6 losses (013),
and 3 copy neutral loss of heterozygosity (CNLOH) (08). The most
frequent CNA were trisomy 7 (18%) and 18 (18%); gains of 1q (47%),
3 (35%), 6p (29%), 9p24.3p24.1 (18%), 9p13.2 (29%), 12p13.33
q21.1 (18%), 17q (24%), 18q (29%), and 19q13.32q14.43 (35%); and
losses of 9p21.3 (CDNK2A/B) (59%), 6q21 (PRDM1) (76%), 6q22.31
160
-
SUPPLEMENT ABSTRACTS
q24.3 (TNFAIP3) (65%), 13q14.2 (DLEU2) (18%) and 17p (TP53) (35%)
(Figure 1B). CNLOH of 9p region was recurrent in 35% of cases.
Moreover, using FISH for JAK2 (9p24) we detected gain in one
additional case, corresponding to a total of 4 cases (24%).
All but five patients received firstline treatment with immu-
nochemotherapy, mostly RCHOP (86%), followed by radiotherapy in
63%. Central nervous system prophylaxis was performed in 79% of
the patients. Complete response rate was 78%. With a median
followup of 8 years, eleven patients relapsed, 3 at CNS. Progression
free survival at 5 years was 45% (95% CI: 3262). Thirtythree (53%)
patients died. Overall survival at 5 years was 50% (95% CI: 3767).
Conclusions: TDLBCL is a poor risk type of DLBCL with a typical
nonGCB subtype although with particular genetic features.
The research was funded by: This work was supported by the Insti-
tuto de Salud Carlos III, the Ministerio de Ciencia e Innovación and
the European Regional Development Fund “Una manera de hacer
Europa” [grants numbers PI16/00420 and PI19/00887 to ALG and
EG and PI17/01061 to SB ]; CIBERONC [grants numbers CB16/12/
00334 and CB16/12/00225]; Fundación AECC/CIBER [grant number
PROYE18020BEA]. CL is supported by Agència de Gestió d'Ajuts
Universitaris i de Recerca (AGAUR) [grant number 2018BP00055].
Keywords: Aggressive Bcell nonHodgkin lymphoma, Extranodal
nonHodgkin lymphoma, Pathology and Classification of Lymphomas
No conflicts of interest pertinent to the abstract.
104 |A GENE SIGNATURE TO PREDICT RISK OF
TRANSFORMATION IN PATIENTS WITH FOLLICULAR
LYMPHOMA
I. FernandezMiranda
1
, M. Dominguez
1
, L. Pedrosa
1
, S. Gomez
1
, J.
GonzalezRincon
1
, B. Espinet
2
, F. Climent
3
, F. de la Cruz
4
, P. Martin
Acosta
5
, L. Colomo
2
, A. Salar
6
, M. GarciaCosio
7
, F. R. GarciaArroyo
8
,
M. Llanos
9
, N. Yanguas
1
, S. Sequero
10
, S. Mercadal
11
, B. Navarro
12
, M.
A. Piris
13
, M. Mollejo
14
, M. Provencio
15
, M. SanchezBeato
1
1
Instituto de Investigación Sanitaria Puerta de HierroSegovia de Arana,
Lymphoma Research Group, Majadahonda, Spain,
2
Hospital del Mar,
Pathology Service, Barcelona, Spain,
3
Hospital Universitari de Bellvitge
IDIBELL, Pathology Department, Bellvitge, Spain,
4
Hospital Universitario
Virgen del Rocío, Hematology Department, Sevilla, Spain,
5
Instituto de
Investigación Sanitaria Puerta de HierroSegovia de Arana, Research
Group in Molecular Cancer Pathology, Majadahonda, Spain,
6
Hospital del
Mar, Hematology Service, Barcelona, Spain,
7
Hospital Universitario
Ramón y Cajal, Pathology Department, Madrid, Spain,
8
Complejo Hospi-
talario de Pontevedra, Oncology Department, Pontevedra, Spain,
9
Hos-
pital Universitario de Canarias, Oncology Department, Tenerife, Spain,
10
Hospital Universitario San Cecilio, Oncology Department, Granada,
Spain,
11
Institut Catala d’OncologiaIDIBELL, Clinic Hematology Depart-
ment, Bellvitge, Spain,
12
Hospital Universitario Puerta de Hierro, Hema-
tology Department, Majadahonda, Spain,
13
Hospital Fundación Jiménez
Díaz, Pathology Department, Madrid, Spain,
14
Complejo Hospitalario de
SUPPLEMENT ABSTRACTS
-
161
Toledo, Pathology Department, Toledo, Spain,
15
Hospital Universitario
Puerta de Hierro, Oncology Department, Majadahonda, Spain
Follicular lymphoma (FL) is an indolent but mainly incurable disease.
Histological transformation to diffuse large B cell lymphoma is
associated with rapid progression, treatment resistance and poor
prognosis. The ability to identify patients at higher risk of trans-
formation at the time of diagnosis would imply a relevant advance.
Prospective identification of transformationpotential would also
serve for guiding treatment and monitoring of patients. We aimed to
validate the prognostic signature previously identified by our group
(GonzálezRincón et al., 2019) to stratify patients according to their
risk of transformation.
We conducted targeted massive parallel sequencing (including
77 genes) on new diagnostic samples from 21 pretransformed (pre
tFL) and 30 nontransformed FL (ntFL) patients. Additionally, our
previously published cohort of 42 samples (22 pretFL and 20 ntFL)
was included to enable risk analysis. Cox proportional hazards
regression and KaplanMeier analysis were performed joining both
cohorts (93 samples) to develop risk models.
Comparative analysis revealed that pretFL showed more mu-
tations than ntFL samples (9.5 vs. 8). The variant allele frequency
(VAF) in pretFL samples was lower than in ntFL (pretFL: 24% vs.
ntFL: 30%; ttest p <0.001), resulting in a higher proportion of
subclonal mutations (<20% VAF) per sample (pretFL: 38% vs. ntFL:
24%; ttest p =0.034). Importantly, patients with subclonal muta-
tions had a higher risk of transformation (p =0.022) by the univariate
Cox analysis. The detection of mutations in HIST1H1E (p <0.001),
NOTCH2 (p <0.001), IRF8 (p =0.005) and UBE2A (p =0.006)
(HIST1H1E,NOTCH2 &UBE2A previously reported by González
Rincón et al., 2019) were statistically associated with transformation
by the multivariate Cox analysis. Inclusion of the Follicular
Lymphoma International Prognostic Index (FLIPI) into the multivar-
iate Cox model (intermediate FLIPI: p =0.024; high FLIPI: p =0.001;
HIST1H1E: p <0.001; NOTCH2: p =0.002; UBE2A: p =0.012; IRF8:
p=0.029) rendered a classification of the samples into three risk
groups, with distinct transformation probabilities at 5 years (85% for
the highrisk group, 46% for the intermediaterisk group and 22% for
the lowrisk group; p <0.001) by the KaplanMeier analysis.
In summary, genomic analysis on FL samples have enabled the
association of mutated genes with higher risk of transformation. We
have also demonstrated that mutations below 20% VAF in FL sam-
ples at diagnosis are associated with transformation. Integration of
the mutational status with clinical risk factors into a predictive model
improves the risk stratification and could be useful for identifying
patients at higher risk of transformation.
The research was funded by: The ISCIIIMINECO AESFEDER (Plan
Estatal de I+D+I 20082011 and 20132016) (DTS17/00039, PI17/
00272); GILEAD (GL18/00019) and Comunidad de Madrid (B2017/
BMD3778). Centro de Investigación Biomédica en Red de Cáncer
(CIBERONC) (CB16/12/00291)
Keywords: Genomics, Epigenomics, and Other Omics, Risk Models,
Indolent nonHodgkin lymphoma
No conflicts of interest pertinent to the abstract.
105 |MUTATIONAL LANDSCAPE OF MARGINAL ZONE BCELL
LYMPHOMAS OF VARIOUS ORIGIN: ORGANOTYPIC
ALTERATIONS AND DIAGNOSTIC POTENTIAL FOR ASSIGNMENT
OF ORGAN ORIGIN
S. Dirnhofer
1
, V. Vela
1
, D. Juskevicius
1
, T. Menter
1
, A. Tzankov
1
1
University Hospital Basel, Pathology, Basel, Switzerland
162
-
SUPPLEMENT ABSTRACTS
Background: Marginal zone lymphomas (MZL) comprise nodal
(NMZL), splenic (SMZL), and extranodal (EMZL) variants, accounting
for 10%, 15% and 75%, respectively. MZL have no diseasedefining
phenotype and the diagnostic borders among each other and to
other small Bcell lymphomas are blurred. In disseminated cases,
determination of MZL origin can be impossible. MZL are known
to bear rather typical siteoforigin translocations, yet their muta-
tional landscape at the nucleotide level has not been integratively
analyzed.
Methods: This metaanalysis aims to concisely summarize the ge-
netic landscape with respect to somatic mutations of NMZL, EMZL
(dura mater, ocular adnexa, salivary glands, thyroid, lung, stomach,
skin) and SMZL. A systematic PubMed search for studies reporting
on sequenced MZL was executed. A dataset containing 25 pub-
lications comprising 6016 variants from 1663 patients was created.
Genomic information was extracted from the selected studies and
uniformed to the GRCh38hg38 genome by applying LiftOver
UCSC Genome Browser. The missing information on variants such
as genomic location and reference sequence variant effect anno-
tation was obtained with the GRCh38 assembly of Variant Effect
Predictor by Ensemble and Annovar software. The number of
mutated and unmutated cases was retrieved and calculated from
the variant tables with somatic mutations. A shortlist was gener-
ated for mutated genes with a stringent frequency cutoff of
>7.5%.
Results: In SMZL, KLF2 (18%, 103/567) and NOTCH2 (16%, 118/
725) were the most frequently mutated genes. Pulmonary MZL
and NMZL displayed recurrent mutations in chromatinmodifying
genes, especially KMT2D (25%, 13/51, and 20%, 20/98, respec-
tively), next to TNFAIP3 (19%, 12/64, and 14%, 12/88, respec-
tively). Ocular adnexal and dura mater MZL displayed a particular
high frequency of mutations in TNFAIP3 (39%, 113/293, and 45%,
5/11, respectively). MZL of the thyroid had a uniquely high prev-
alence for TET2 mutations (61%, 11/18), next to mutations of
TNFRSF14 (44%, 8/18). Cutaneous MZL showed a particular
accumulation of FAS (63%, 24/38) and SLAMF1 mutations (24%, 9/
38). Finally, TBL1XR1 (24%, 14/58) was the most commonly
mutated gene in MZL of the salivary glands, next to GPR34 (16%,
9/58).
Assigned to pathways and functions, mutations affected NF‐κB and
NOTCH signalling as well as chromatin modification. Mutations of
NF‐κB and NOTCH signalling genes were rather mutually exclusive,
with only 140 cases showing cooccurrence, 553 being exclusively
mutant in either pathway compounds, and 242 being wildtype (p =
1.07E9; Fisher's test); the same applied to NF‐κB member and
chromatin modifier mutations.
Conclusion: Mutations of distinct genes show organoforigin
preferential distribution among MZL which may help assigning MZL
derivation in difficult cases and possibly pave the way for novel
tailored treatment concepts.
Keywords: Pathology and Classification of Lymphomas
No conflicts of interest pertinent to the abstract.
106 |CYTIDINE DEAMINASES SHAPE THE GENOME OF
GERMINAL CENTER B CELL DERIVED LYMPHOMA
M. Ren
1
, E. Sidiropoulou
1
, R. N. Tasakis
2
, E. Donato
3
, I. Gonzalez
Menendez
4
, C. E Busse
5
, T. J Luck
6
, A. Dolnik
6
, L. Bullinger
6
,
A. Trumpp
3
, L. QuintanillaMartinez
4
, M. Kreuz
7
, B. Chapuy
8
, D.
Hübschmann
9
, R. Siebert
10
, F N. Papavasiliou
2
, S. Sander
1
1
German Cancer Research Center (DKFZ)/National Center for Tumor
Diseases Heidelberg (NCT), Division of Adaptive Immunity and
Lymphoma, Heidelberg, Germany,
2
German Cancer Research Center
(DKFZ), Division of Immune Diversity, Heidelberg, Germany,
3
German
Cancer Research Center (DKFZ) and DKFZZMBH Alliance, Division of
Stem Cells and Cancer, Heidelberg, Germany,
4
Eberhard Karls University
of Tübingen and Comprehensive Cancer Center, Tübingen University
Hospital, Institute of Pathology and Neuropathology, Department of Pa-
thology, Tübingen, Germany,
5
German Cancer Research Center (DKFZ),
Division of B cell Immunology, Heidelberg, Germany,
6
Campus Virchow
Klinikum, Berlin, Charité Universitätsmedizin Berlin, corporate member
of Freie Universität Berlin and HumboldtUniversität zu Berlin, Depart-
ment of Hematology, Oncology, and Tumorimmunology, Berlin, Germany,
7
Universität Leipzig, Institute for Medical Informatics, Statistics and
Epidemiology (IMISE), Leipzig, Germany,
8
University Medical Center
Göttingen, Department of Hematology and Medical Oncology, Göttingen,
Germany,
9
German Cancer Research Center (DKFZ)/National Center for
Tumor Diseases Heidelberg (NCT), Heidelberg Institute for Stem Cell
Technology and Experimental Medicine (HISTEM gGmbH), Heidelberg,
Germany,
10
Ulm University and Ulm University Medical Center, Depart-
ment of Human Genetics, Ulm, Germany
Introduction: Most human lymphomas have their origin in the
germinal center (GC) reaction where the cytidine deaminase AID
(encoded by the AICDA gene) targets the B cell genome. Although
AID's activity at nonimmunoglobulin (Ig) genes is reported, this off
target effect is not the only source of tumorigenic mutations in
lymphoma patients. Thus, we aimed for a better understanding of
AID independent mechanisms of mutagenesis in GC B cell derived
lymphomagenesis.
Methods: Genetic Aicda knockout was combined in a preclinical
mouse lymphoma model characterized by GC B cell specific MYC
and PI3K coactivation. Indepth characterization of premalignant
and malignant GC B cells was achieved by flow cytometry, immu-
nohistology and next generation sequencing technologies. The mu-
rine findings were confirmed using data derived from human B cells
and lymphoma cells provided by the ICGC MMMLseq consortium.
Results: In young mice, AID deficiency promoted GC formation,
although GC B cell proliferation, survival and differentiation were
similar in AID proficient and deficient animals. Upon aging, GC B cell
derived lymphomagenesis was unperturbed in the absence of AID. In
AID deficient tumors the lack of mutations in Ig genes was in contrast
to the increased mutation load in nonIg genes compared to AID
proficient lymphoma. Gene expression profiling and the detection of
distinct mutational signatures pointed to the function of the cytidine
deaminase APOBEC1 in murine AID deficient lymphoma.
SUPPLEMENT ABSTRACTS
-
163
The mining of human data uncovered the expression of APO-
BEC3 family members in human B cells, including APOBEC3B induc-
tion in GC B cells, thereby mimicking murine Apobec1 expression
kinetics. Although APOBEC3B expression levels were variable across
different GC B cell derived lymphoma entities, the positive correla-
tion of its expression and presence of APOBEC related DNA signa-
tures indicates its relevance in human lymphomagenesis.
Conclusions: Our research provides experimental evidence of APO-
BEC mediated DNA mutagenesis in an autochthonous mouse lym-
phoma model and supports these findings in lymphoma patient data
sets. Thus, we unveiled AID independent transformation in lym-
phoma prone GC B cells and highlight APOBEC enzymes as mutation
driver in GC B cell derived lymphomagenesis.
The research was funded by: the Deutsche Krebshilfe (Max Eder
Program 111349 to S.Sander), the Deutsche Jose Carreras Leukä-
miestiftung (11/2017 to S.Sander), FOR2674, SFB873 funded by the
DFG, the DKTK Joint Funding “RiskYAML” and the Dietmar Hopp
Foundation (to A.Trumpp) and SFB1074 funded by the DFG (to R.
Siebert).
Keywords: Tumor Biology and Heterogeneity, Aggressive Bcell non
Hodgkin lymphoma
No conflicts of interest pertinent to the abstract.
INDOLENT LYMPHOMAS
107 |SAFETY AND EFFICACY OF ZANUBRUTINIB IN PATIENTS
WITH RELAPSED/REFRACTORY MARGINAL ZONE LYMPHOMA
(MAGNOLIA PHASE 2 STUDY)
J. Trotman
1
, A. Tedeschi
2
, K. Linton
3
, P. McKay
4
, B. Hu
5
, H. Chan
6
, J.
Jin
7
, M. SobierajTeague
8
, P. L. Zinzani
9
, M. Coleman
10
, P. Browett
11
,
X. Ke
12
, M. Sun
13
, R. Marcus
14
, C. Portell
15
, C. Thieblemont
16
, K.
Zhou
17
, A. M. Liberati
18
, E. Bachy
19
, F. Cavallo
20
, Rég. Costello
21
, S.
Iyengar
22
, R. Marasca
23
, H. Mociková
24
, J. S. Kim
25
, D. Talaulikar
26
,
M. Co
27
, W. Zhou
27
, J. Huang
27
, S. Opat
28
1
Concord Repatriation General Hospital, University of Sydney, Oncology,
Concord, Australia,
2
ASST Grande Ospedale Metropolitano Niguarda,
Hematology, Milan, Italy,
3
The Christie, Hematology, Manchester, UK,
4
Beatson West of Scotland Cancer Centre, Oncology, Glasgow, UK,
5
Levine Cancer Institute/Atrium Health, Oncology, Charlotte, USA,
6
North
Shore Hospital, Haematology, Auckland, New Zealand,
7
The First
Affiliated Hospital, Zhejiang University, Hematology, Hangzhou, China,
8
Flinders Medical Centre, Haematology, Bedford Park, Australia,
9
Institute
of Hematology “Seràgnoli” University of Bologna, Hematology, Bologna,
Italy,
10
Clinical Research Alliance, Hematology, Lake Success, USA,
11
Auckland City Hospital, Haematology, Grafton, New Zealand,
12
Peking
University Third Hospital, Hematology, Beijing, China,
13
Institute of
Hematology & Blood Diseases Hospital, Chinese Academy of Medical
Sciences, Peking Union Medical College, Hematology, Tianjin, China,
14
Sarah Cannon Research Institute UK, Oncology, London, UK,
15
University of Virginia Health System, Hematology/Oncology,
Charlottesville, USA,
16
APHP, Hôpital SaintLouis, Hematooncology, Paris
University Diderot, Hematology/Oncology, Paris, France,
17
Henan Cancer
Hospital, Oncology, Zhengzhou, China,
18
Azienda Ospedaliera Santa
Maria Di Terni, Oncology, Terni, Italy,
19
Centre Hospitalier Lyon Sud,
Pierre Bénite, Hematology, Rhone, Italy,
20
Azienda Ospedaliera Città della
Salute e della Scienza di Torino, Hematology, Torino, Italy,
21
Hôpital de la
Conception APHM, Hematology, Marseille, France,
22
Royal Marsden
Hospital, Haematology, London, UK,
23
AOU Policlinico di Modena, He-
matology, Modena, Italy,
24
Fakultní nemocnice Královské Vinohrady,
Hematology, Praha 10, Czech Republic,
25
Severance Hospital, Hematol-
ogy, Seoul, Korea,
26
The Canberra Hospital, Haematology, Canberra,
Australia,
27
BeiGene (Beijing) Co., Ltd., Beijing, China and BeiGene USA,
Inc., Hematology, San Mateo, USA,
28
Monash Health, Monash University,
Haematology, Clayton, Australia
Introduction: Zanubrutinib is a potent, specific nextgeneration BTK
inhibitor with high selectivity for BTK vs the TECand EGFRfamily
kinases, which may be related to offtarget toxicities.
Methods: This is a singlearm, multicenter study of adults with R/R
MZL who previously received 1 prior therapy including 1 CD20
antibody regimen. All received zanubrutinib 160 mg bid until disease
progression/unacceptable toxicity. Primary endpoint was overall
response rate (ORR) by independent review committee (IRC). Sec-
ondary endpoints include investigatorassessed (INV) ORR, duration
of response (DOR), progressionfree survival (PFS), and safety.
Results: By January 11, 2021, 68 patients (pts) were enrolled and
treated. Median age was 70 years (range, 3795). Subtypes included
extranodal (38%), nodal (38%), splenic (18%), and indeterminate in
6% of pts. Median number of prior therapies was 2 (range, 16), and
32% had disease refractory to last therapy.
Median duration of drug exposure was 59.1 weeks (range, 3.7
84.1). At a median followup of 15.5 months (range, 1.621.7), INV ORR
was 74% with a CR rate of 24%. Responses were observed in all sub-
types. Median DOR and PFS were not reached. IRC review is ongoing.
Twentyeight (41%) pts discontinued treatment. The most com-
mon treatmentemergent AEs reported in 10% of pts were diarrhea
(22%), bruising (21%), and constipation (15%). Neutropenia was the
most common grade 3 AE (10%). Allgrade AEs of interest included
neutropenia (13%), thrombocytopenia (13%), atrial fibrillation/flutter
(3%), and hypertension (3%). No major/serious hemorrhage was re-
ported. No AEs led to dose reductions.
Conclusions: Zanubrutinib demonstrated high response rates and
durable disease control with a favorable safety profile in pts with R/R
MZL.
EA previously submitted to EHA 2021.
The research was funded by: BeiGene (Beijing) Co., Ltd., Beijing,
China and BeiGene USA, Inc., San Mateo, CA, USA
Keywords: Indolent nonHodgkin lymphoma
Conflicts of interests pertinent to the abstract
J. Trotman
Research funding: BeiGene, Celgene, Roche, Takeda, PCYC, Janssen
164
-
SUPPLEMENT ABSTRACTS
A. Tedeschi
Consultant or advisory role: AbbVie, AstraZeneca, Janssen, BeiGene
Other remuneration: Speakers' Bureau: AbbVie, AstraZeneca, Jans-
sen, BeiGene
K. Linton
Consultant or advisory role: BeiGene, Celgene, Gilead, Karyopharm,
Roche, Takeda
Honoraria: Roche
Research funding: Genmab, BeiGene, Pharmacyclics, Roche
Educational grants: Bristol Meyers Squibb, Roche, Janssen, Celgene
P. McKay
Consultant or advisory role: Celgene, Janssen, BeiGene, Kite
Honoraria: Roche, Recordati
B. Hu
Consultant or advisory role: Kite, Cellectar
Research funding: Roche/Genetech, Celgene, BeiGene
H. Chan
Consultant or advisory role: Eusa, AbbVie, Janssen
Research funding: Janssen
P. L. Zinzani
Consultant or advisory role: Verastem, Celltrion, Gilead, Janssen
Cilag, Bristol Meyers Squibb, Sanofi, Servier, Sandoz, MSD, TG
Therapeutics, Takeda, Roche, Eusapharma, Kyowa Kirin, ADC
Therapeutics
Other remuneration: Speakers' Bureau: Verastem, Celltrion, Gilead,
JanssenCilag, Bristol Meyers Squibb, Servier, MSD, TG Therapeutics,
Takeda, Roche, Eusapharma, Kyowa Kirin
M. Coleman
Research funding: AbbVie, Pharmacyclics, AstraZeneca, Bristol
Meyers Squibb, Celgene
P. Browett
Consultant or advisory role: MSD, JanseenCilag
Honoraria: Janssen, Roche
Research funding: Roche, Shire
R. Marcus
Consultant or advisory role: MEI Pharma
C. Portell
Consultant or advisory role: BeiGene, Genentech, Janssen, Kite/
Gilead, Morphosys, Pharmacyclics
Research funding: AbbVie, Genentech, Xencor, Infinity, TG Thera-
peutics, Acerta, Kite, AstraZeneca, SeaGen, VelosBio
C. Thieblemont
Consultant or advisory role: Janssen, Novartis, Gilead, Roche, Cel-
gene/Bristol Myers Squibb
TABLE
SUPPLEMENT ABSTRACTS
-
165
Honoraria: Janssen, Novartis, Gilead, Roche, Celgene/Bristol Myers
Squibb
Educational grants: Roche, Gilead, Celgene, Bristol Myers Squibb,
Novartis
A. M. Liberati
Consultant or advisory role: Amgen, Servier, Celgene
Research funding: Novartis, Janssen, AbbVie, Roche, Amgen,
Celgene, Bristol Meyers Squibb, Takeda, Incyte, Pfizer, BeiGene,
Oncopeptides, AB, Verastem, Karyopharm, Archiegn, CTI Biopharma
Corp, Debiopharm International, Morphosys, Fribrogen, Onconova
Therapeutics Inc.
Educational grants: Roche, Takeda, AbbVie, Novartis, Sanophy Gen-
zyme, Verastem, Bristol Meyers Squibb
F. Cavallo
Consultant or advisory role: Roche
Honoraria: Janssen, Celgene, Gilead
Educational grants: Amgen
S. Iyengar
Consultant or advisory role: Takeda, Gilead, BeiGene
Educational grants: Takeda, Janssen
Other remuneration: Speakers' Bureau: Takeda, Gilead, AbbVie,
Janssen
R. Marasca
Honoraria: AbbVie
D. Talaulikar
Consultant or advisory role: Roche, EUSA pharma, George Clinical
Research funding: Roche
Educational grants: Roche
Other remuneration: Speakers' Bureau: Roche
M. Co
Employment or leadership position: BeiGene
Stock ownership: BeiGene
W. Zhou
Employment or leadership position: BeiGene
Stock ownership: BeiGene
J. Huang
Employment or leadership position: BeiGene
Stock ownership: BeiGene
Educational grants: BeiGene
Other remuneration: Patents, Royalties, OtherIntellectual Property:
BeiGene
S. Opat
Consultant or advisory role: Roche, Janssen, AbbVie, Celgene,
Takeda, Merck, Gilead, Mundipharma, AstraZeneca, CSL
Honoraria: Roche, Janssen, AbbVie, Celgene, Takeda, Merck, Gilead,
AstraZeneca
Research funding: BeiGene, Roche, Janssen, AbbVie, Takeda, Merck,
Gilead, Epizyme, AstraZeneca
Educational grants: Roche
108 |LONG TERM OUTCOMES OF GASTRIC MALT
LYMPHOMA TREATED WITH RADIOTHERAPY: A MULTICENTRE
RETROSPECTIVE STUDY
C. Smith
1
, S. A. Gupta
2
, Y. S Chin
3
, S. R Thompson
1
1
Prince of Wales Hospital, Department of Radiation Oncology, Randwick,
Australia,
2
Calvary Mater Hospital, Department of Radiation Oncology,
Newcastle, Australia,
3
St George Hospital, Department of Radiation
Oncology, Kogarah, Australia
Introduction: Gastric mucosaassociated lymphoid tissue (MALT)
lymphoma is a rare disease. Treatment has evolved over time, how-
ever radiotherapy remains an important definitive modality. We
assessed the long term outcomes of patients treated with early stage
gastric MALT marginal zone (MZ) lymphoma treated with definitive
radiotherapy at three Australian institutions.
Methods: We conducted a retrospective, multicentre study of pa-
tients with gastric MALT MZ lymphoma treated with radiotherapy
between 01/03/1999 and 29/05/2020. Eligible patients were: age 18
years, treated with curative intent radiotherapy, pathological diagnosis
of MALT MZ lymphoma. Timetoevent outcomes were calculated
from day 1 of radiotherapy. Toxicities were graded as per CTCAEv4.0.
Results: There were 33 eligible patients. Median age was 64 (range
37 82). 31 (94%) patients had Lugano stage I disease, 2 (6%) were
stage II. 20 (61%) patients previously received treatment (16 H. Py-
lori eradication (HPE), 2 chemotherapy, 1 surgery, and 1 HPE +
chemotherapy). Median prescribed RT dose was 30Gy (range 20
42) in 15 fractions (range 10 28).
Complete response (CR) was reported in 30/31 (96.7%) of
endoscopically assessed cases. During median follow up of 66.2
months (IQR 22119 months), estimated 5 and 10 year local relapse
free survival (LRFS) were 92.6% (95% CI: 83100) and 92.6% (95%
CI: 83100); distant relapse free survival (DRFS) 95.8% (95%CI 88.2
100) and 64.7% (95%CI 43.496.4); freedom from treatment failure
(FFTF) 92.6% (95%CI; 83.1100) and 62.5% (95%CI; 41.793.7); and
progression free survival (PFS) 89.3% (95%CI; 78.4100) and 50.2%
(95%CI; 29.186.6), respectively. There were 6 documented re-
currences; one local, four distant, and both in one patient; two cases
were high grade recurrences. Radiotherapy dose (<30 vs 30Gy),
previous H pylori eradication, or previous treatment failure were not
associated with inferior LRFS, DRFS or PFS on multivariate analysis.
5 and 10 year OS were 92.4% and 73.5% respectively. There were 2
acute grade 3 toxicities (1 anorexia, 1 fatigue) and no severe late
toxicities or treatment related deaths.
Conclusions: Patients with gastric MALT lymphoma treated with
definitive radiotherapy have excellent outcomes in terms of both local
control and survival. A significant proportion in long term follow up
developed distant low grade disease, either relapsed or new primary
MZL. Extended follow up should be considered in these patients.
Treatment is well tolerated with minimal toxicity. Radiotherapy re-
mains an important modality in the treatment of this disease.
Keywords: Indolent nonHodgkin lymphoma Radiation Therapy
No conflicts of interest pertinent to the abstract.
166
-
SUPPLEMENT ABSTRACTS
109 |CHARACTERISTICS OF PATIENTS ACHIEVING COMPLETE
OR PARTIAL RESPONSE (CR/PR) WITH TAZEMETOSTAT (TAZ) IN
WILDTYPE RELAPSED/REFRACTORY (R/R) FOLLICULAR
LYMPHOMA (FL)
C. L. Batlevi
1
, G. Salles
2
, H. Tilly
3
, A. Chaidos
4
, P. McKay
5
, T. Phillips
6
,
S. Assouline
7
, P. Campbell
8
, V. Ribrag
9
, G. Laurent Damaj
10
, M.
Dickinson
11
, W. Jurczak
12
, M. Kaźmierczak
13
, S. Opat
14
, J. R.
Radford
15
, A. Schmitt
16
, A. Rajarethinam
17
, G. Shang
18
,
F. Morschhauser
19
1
Memorial Sloan Kettering Cancer Center, Lymphoma Service, Department
of Medicine, New York, USA,
2
LyonSud Hospital, University of Lyon, He-
matology, PierreBénite, France,
3
Centre Henri Becquerel and Rouen Uni-
versity, Department of Haematology and INSERM U1245, Rouen, France,
4
Imperial College Healthcare NHS Trust, Hammersmith Hospital, Depart-
ment of Medicine, London, UK,
5
Beatson West of Scotland Cancer Centre,
Department of Hematology, Glasgow, UK,
6
University of Michigan, Hema-
tology and Oncology, Ann Arbor, USA,
7
Division of Hematology, Sir Mor-
timer B. DavisJewish General Hospital, Oncology, Montreal, Canada,
8
Barwon Health, University Hospital Geelong, Department of Clinical
Haematology, Geelong, Australia,
9
Gustave Roussy, Hematology, Villejuif,
France,
10
Hematology Institute University Hospital School of Medicine,
Hematology, Caen, France,
11
Peter MacCallum Cancer Centre, Royal Mel-
bourne Hospital, Department of Clinical Haematology, Melbourne,
Australia,
12
Maria SklodowskaCurie National Research Institute of
Oncology, Department of Hematology, Kraków, Poland,
13
Poznań Univer-
sity of Medical Sciences, Department of Hematology and Bone Marrow
Transplantation, Poznań, Poland,
14
Monash University, Department of
Haematology, Victoria, Australia,
15
University of Manchester, NIHR Man-
chester Clinical Research Facility, Manchester Academic Health Science
Centre, The Christie NHS Foundation Trust,, Department of Medical
Oncology, Manchester, UK,
16
Institut Bergonié, Department of Hematology,
Bordeaux, France,
17
Epizyme, Inc., Clinical Data Management, Cambridge,
USA,
18
Epizyme, Inc., Medical Affairs , Cambridge , USA,
19
Groupe de
Recherche sur les formes Injectables et les Technologies Associées, CHU de
Lille, Université de Lille, Oncology, Lille, France
Introduction: Enhancer of zeste homolog 2 (EZH2) epigenetic modifier
expressed within germinal centers is an important regulator of FL
growth and survival. TAZ is an EZH2 inhibitor approved for R/R FL with
heightened overall response rates (ORRs) in mutant (MT) EZH2 but
similar progressionfree survival (PFS) in wildtype (WT) and MT EZH2
cohorts. Pivotal phase 2 study identified ORRs (CR/PR) of 35% (19/54)
and 69% (31/45) in WT and MT EZH2 cohorts, respectively; PFS was
11.1 mo in WT and 13.8 mo in MT EZH2 cohorts. This exploratory
analysis assessed if baseline demographics or disease characteristics
correlate with response to TAZ in the WT EZH2 FL cohort.
Methods: Detailed methods of this openlabel multicenter phase
2 study (NCT01897571) are described in Morchhauser et al. Lancet
Oncol 2020. Oral TAZ 800 mg twice daily was assessed in adults with FL
after 2 prior systemic therapies. Baseline demographics and disease
characteristics were summarized using descriptive statistics.
Results: Of 99 patients (pts) with WT or MT EZH2, 19 pts with WT
EZH2 who received a median of 3 prior lines of therapy responded (2
CR, 17 PR). In general, WT EZH2 group had more pts with highrisk
features than the MT EZH2 group. Baseline characteristics of pts in
the WT EZH2 group who achieved a response were similar to pts with
MT EZH2 who responded, as well as the general population (Table).
The number of pts with highrisk features, such as progression of
disease within 24 mos (POD24), refractory to rituximabcontaining
regimen, and double refractory, were similar in the WT and MT
EZH2 responder groups, respectively. Pts with refractoriness to last
therapy represented 26.3% and 51.6% of WT and MT EZH2 re-
sponders, but the populations were small.
Conclusions: Characteristics of responders in the WT EZH2 FL cohort
were reflective of the overall population, with a broad distribution of
disease severity at baseline. Responders with WT EZH2 included pts
with highrisk features, such as POD24, refractoriness to rituximab
based regimens, or double refractory disease. Response to TAZ in pts
with WT EZH2 R/R FL appears to be independent of baseline clinical
factors; however, small numbers preclude a definitive assessment.
Additional correlative molecular analyses are in progress.
The research was funded by: Epizyme, Inc.
Keywords: Indolent nonHodgkin lymphoma, Therapeutics and Clin-
ical Trials in Lymphoma Other
Conflicts of interests pertinent to the abstract
C. L. Batlevi
Consultant or advisory role: Life Sci, GLG, Juno/Celgene, Seattle
Genetics, Kite, Karyopharm, TG Therapeutics
Stock ownership: None over $10,000 not including potential holdings
in retirement mutual funds
Honoraria: Dava Oncology
TABLE: Baseline Disease Characteristics of Responders
SUPPLEMENT ABSTRACTS
-
167
Research funding: Janssen, Novartis, Epizyme, Xynomics, Bayer,
Autolus, Roche
G. Salles
Consultant or advisory role: Abbvie, Autolus, Bristol Myers Squibb,
Celgene, Debiopharm, Genmab, Gilead, F. HoffmannLa Roche, Epi-
zyme, Janssen, Karyopharm, Kite Pharma, and Takeda, and has
participated in educational events for Abbie, Amgen, Celgene, Gilead,
and Janssen
Honoraria: Abbvie, Autolus, Bristol Myers Squibb, Celgene, Debio-
pharm, Genmab, Gilead, F. HoffmannLa Roche, Epizyme, Janssen,
Karyopharm, Kite Pharma, and Takeda, and has participated
in educational events for Abbie, Amgen, Celgene, Gilead, and Janssen
H. Tilly
Consultant or advisory role: AstraZeneca; Karyopharm Therapeutics;
Roche
Honoraria: Celgene; Roche/Genentech; SERVIER
Research funding: Celgene (Inst)
Educational grants: Roche
P. McKay
Consultant or advisory role: BeiGene, Celgene, Gilead, Janssen,
Roche, and Takeda
Educational grants: Janssen and Takeda
Other remuneration: Fees for lectures and Speakers bureau Gilead,
Janssen, Roche, and Takeda
T. Phillips
Consultant or advisory role: AbbVie, AstraZeneca, Bayer, BeiGene,
Bristol Myers Squibb, Cardinal Health, Incyte, Karyopharm, Phar-
macyclics, and Seattle Genetics
Research funding: AbbVie and Bayer
Educational grants: Incyte
S. Assouline
Consultant or advisory role: AbbVie, AstraZeneca, BeiGene, F.
HoffmannLa Roche, Janssen, and Pfizer Inc
Honoraria: AbbVie, AstraZeneca, BeiGene, F. HoffmannLa Roche,
Janssen, and Pfizer Inc
Research funding: BeiGene, F. HoffmannLa Roche, and Takeda
Other remuneration: Speakers Bureau: AbbVie, AstraZeneca, and
Janssen
P. Campbell
Consultant or advisory role: Amgen, AstraZeneca, CSL Behring,
Janssen, Novartis, and Roche
Stock ownership: argenX and Epizyme
Research funding: Amgen, Celgene (BMS), Janssen, Novartis, and
Roche
V. Ribrag
Consultant or advisory role: Bristol Myers Squibb, Epizyme, Immune
Design, Incyte, Infinity, MSD, Nanostring, Pharmamar, Roche/Gen-
entech, Servier, AstraZeneca, Epizyme, F. HoffmannLa Roche, Gilead,
Stock ownership: argenX and Epizyme
Research funding: arGENXBVBA, argenX, and Epizyme
G. Laurent Damaj
Consultant or advisory role: Accord, Iqone, Roche, and Takeda
Honoraria: Accord, Roche, and Takeda
Educational grants: AbbVie, Pfizer, Roche, and Takeda
M. Dickinson
Consultant or advisory role: Gilead, Janssen, Merck Sharp & Dohme,
Novartis, and Roche
Honoraria: Gilead, Janssen, Novartis, and Roche
Research funding: Gilead and Novartis
Other remuneration: speakers’ bureaus for board of directors for
Gilead, Janssen, Novartis, and Roche
W. Jurczak
Consultant or advisory role: Acerta, Afimed, AstraZeneca, BeiGene,
Epizyme, European Medicines Agency, Janssen, SanofiNovartis
Research funding: Acerta, Bayer, BeiGene, Celgene, Gilead, Janssen
China, MEI Pharma, Merck, MorphoSys, Nordic Nanovecotr, Phar-
macyclics, Roche, Servier, Takeda, and TG Therapeutics
M. Kaźmierczak
Consultant or advisory role: Acerta, Afimed, AstraZeneca, Bei-
Gene, Epizyme, European Medicines Agency, Janssen, Sanofi
Novartis
Research funding: Acerta, Bayer, BeiGene, Celgene, Gilead, Janssen
China, MEI Pharma, Merck, MorphoSys, Nordic Nanovecotr, Phar-
macyclics, Roche, Servier, Takeda, and TG Therapeutics
S. Opat
Consultant or advisory role: AbbVie, CSL, F. HoffmanLa Roche,
Gilead, Janssen, Merck, and Mundipharma
Honoraria: AbbVie, AstraZeneca, Celgene, CSL, Gilead, Janssen,
Merck, Mundipharma, Roche, and Takeda
Other remuneration: advisory board or board of directors for Abb-
Vie, AstraZeneca, Celgene, CSL, Gilead, Janssen, Merck, Mundi-
pharma, Roche, and Takeda
J. R. Radford
Consultant or advisory role: Bristol Myers Squibb, Kite Pharma,
Novartis, and Takeda
Stock ownership: AstraZeneca and GlaxoSmithKline
Research funding: ADCT, Pfizer, and Takeda
Other remuneration: speakers’ bureau or board of directors for
ADCT, Bristol Myers Squibb, Seattle Genetics, and Takeda
A. Schmitt
Consultant or advisory role: advisory board or board of directors for
Celgene
Honoraria: Janssen and Roche
A. Rajarethinam
Employment or leadership position: Epizyme, Inc.
Stock ownership: Epizyme, Inc.
G. Shang
Employment or leadership position: Medivation, Pfizer, Epizyme, Inc.
Stock ownership: Epizyme, Inc.
168
-
SUPPLEMENT ABSTRACTS
F. Morschhauser
Consultant or advisory role: F. HoffmannLa Roche, Genentech,
Servier, AbbVie, Celgene, Epizyme, and Gilead
Honoraria: Janssen
110 |ATEZOLIZUMAB +OBINUTUZUMAB +VENETOCLAX IN
PATIENTS WITH RELAPSED OR REFRACTORY FOLLICULAR
LYMPHOMA: PRIMARY ANALYSIS OF A PHASE 2 TRIAL FROM
LYSA
G. Cartron
1
, E. Bachy
2
, S. Guidez
3
, E. Gyan
4
, R. Gressin
5
, N.
Morineau
6
, D. Sibon
7
, O. Casasnovas
8
, S. Le Gouill
9
, H. Tilly
10
, L.
Ysebaert
11
, J. M. Schiano de Colella
12
, P. Feugier
13
, E. Nicolas
Virelizier
14
, C. Haioun
15
, G. Damaj
16
, K. Tarte
17
, C. Laurent
18
, R.
Houot
19
, C. Thieblemont
20
, F. Morschhauser
21
, C. Herbaux
1
1
CHU Montpellier, Hématologie Clinique, Montpellier, France,
2
CHU,
Hematology, Lyon, France,
3
CHU, Hematology, Poitiers, France,
4
CHU,
Hematology, Tours, France,
5
CHU, Hematology, Grenoble, France,
6
CHD
Vendée, Hematology, La Roche sur Yon, France,
7
Necker, Hematology,
Paris, France,
8
CHU, Hematology, Dijon, France,
9
CHU, Hematology,
Nantes, France,
10
CHB Unicancer, Hematology, Rouen, France,
11
Oncopole, Hematology, Toulouse, France,
12
IPC, Hematology, Marseille,
France,
13
CHU, Hematology, Nancy, France,
14
CLB, Hematology, Lyon,
France,
15
Mondor, Hematology, Paris, France,
16
CHU, Hematology, Caen,
France,
17
CHU, Pathology, Rennes, France,
18
Oncopole, Pathology,
Toulouse, France,
19
CHU, Hematology, Rennes, France,
20
St Louis,
Hematology, Paris, France,
21
CHU, Hematology, Lille, France
Introduction: Relapsed and refractory (R/R) Follicular Lymphoma (FL)
treatment remains challenging. Atezolizumab (ATE) and obinutuzumab
(OBI) are monoclonal antibodies acting respectively to inhibit T
lymphocyte exhaustion or by inducing lymphoma cells cytotoxicity,
whereas venetoclax (VEN) is a small molecule inhibiting BCL2.
Combining tumortargeted therapies with agents that enhance anti
tumor immunity represents an attractive treatment paradigm. This
LYSA sponsored multicenter phase 2 trial (NCT03276468) evaluated
ATE, OBI and VEN combination in R/R Bcell lymphomas. Herein, we
present primary efficacy and safety data from the FL cohort.
Methods: Patients 18 years with biopsyconfirmed R/R FL who
failed at least one line of therapy were eligible. OBI was given IV at 1
g on day (D) 1, 8 and 15 of cycle (C) 1 and on D1 from C2 to C8 every
3 weeks. ATE was given IV, 1.2 g every 3 weeks, started at D2 of C1,
then administered at D2 of each cycle for 24 cycles. VEN was given
orally at 800 mg/D at full dose, starting on D8C1 for 24 cycles. The
primary endpoint was the Overall Response Rate (ORR) evaluated by
Lugano criteria at the end of induction (EOI) after 8 cycles of ATE,
OBI and VEN (M6) or at premature treatment discontinuation.
Results: At the time of the primary analysis (08 Jan 2021), 58 FL
patients were enrolled. The median followup was 14.5 months, 45
patients completed induction phase and 34 patients started main-
tenance. Baseline characteristics were: median age, 56 years (3883);
male, 66.1%; Ann Arbor Stage III/IV, 85.7%; FLIPI HR, 47.3%; >2
prior lines of therapy, 32.1%; refractory to last line of prior regimen,
26.8%; and exposed to ASCT, 30.4%. The OMRR at EOI was
measured at 53.6% [41.8%65.1%], including 30.4% of CMR whereas
OMRR at C4 was 75.0% [61.6%85.6%], including 28.6% of CMR.
Best of Response Rate (BOR) was 80.4% [69.6%88.6%] including
35.7% of CMR. To date, 23 patients relapsed after an initial response
(51% of the 45 responders). Thirtyseven patients (63%) received the
full induction treatment. At the time of analysis, a median of 8 cycles
[18] has been administered. A total of 41 (70.7%) patients experi-
enced grade 3–4 adverse event (AE) and 1 had an AE that led to
discontinuation of any drug. AE of grade 3 or more reported in at
least 10% of patients were neutropenia (41.4%), thrombocytopenia
(24.1%) and lymphopenia (22.4%). Of note, two patients experienced
autoimmune colitis (grade 2 and 3) and one patient experience a
grade 2 immunerelated pancreatitis during induction.
Conclusion: ATE, OBI and VEN combo appears to be well tolerated,
with no unexpected toxicity brought by the combination. The ORR at
EOI seems to be comparable to other innovative regiments in this
setting, with durable responses to date.
The research was funded by: Roche, Abbvie
Keywords: Indolent nonHodgkin lymphoma, Combination Therapies,
Immunotherapy
No conflicts of interest pertinent to the abstract.
111 |POLATUZUMAB VEDOTIN +OBINUTUZUMAB +
VENETOCLAX IN PATIENTS WITH RELAPSED/REFRACTORY (R/R)
FOLLICULAR LYMPHOMA (FL): PRIMARY ANALYSIS OF A PHASE
1B/2 TRIAL
R. Bannerji
1
, S. Yuen
2
, T. Phillips
3
, C. Arthur
4
, I. Isufi
5
, P. Marlton
6
, J.
F. Seymour
7
, P. Corradini
8
, A. Molinari
9
, G. Gritti
10
, R. Emmons
11
, J.
Hirata
12
, L. Musick
12
, S. Saha
13
, B. Croft
12
, C. Flowers
14
1
Rutgers Cancer Institute of New Jersey, Section of Hematologic
Malignancies, New Brunswick, New Jersey, USA,
2
The Calvary Mater
Newcastle Hospital, Waratah, Australia,
3
University of Michigan Medical
School, Division of Hematology and Oncology, Ann Arbor, USA,
4
Royal
North Shore Hospital, Sydney, Australia,
5
Yale University, Smilow Cancer
Hospital, Section of Hematology, New Haven, USA,
6
Princess Alexandra
Hospital and University of Queensland, Department of Haematology,
Brisbane, Australia,
7
Peter MacCallum Cancer Centre & Royal Melbourne
Hospital, Department of Haematology, Melbourne, Australia,
8
University of
Milan, Istituto Nazionale dei Tumori, Medical Oncology and Hematology
Department, Milan, Italy,
9
AUSL Romagna, Ospedale degli Infirmi, Dirigente
Medico Ematologia, Rimini, Italy,
10
ASST Papa Giovanni XXIII, UOC
Ematologia, Bergamo, Italy,
11
James Graham Brown Cancer Center,
Louisville, USA,
12
Genentech, Inc., Product Development Oncology, South
San Francisco, USA,
13
F. HoffmannLa Roche Ltd, Product Development
Biometrics, Welwyn Garden City, UK,
14
M.D. Anderson Cancer Center,
Department of Lymphoma/Myeloma, Houston, USA
SUPPLEMENT ABSTRACTS
-
169
Introduction: Polatuzumab vedotin (Pola) +obinutuzumab (G)
demonstrated activity and tolerability in a Phase 1b/2 trial of patients
(pts) with R/R FL (Phillips, et al. Blood 2016). Preclinical studies with
venetoclax (Ven) showed that concurrent treatment with Pola pro-
motes MCL1 degradation, a known mechanism of resistance to Ven,
and enhances in vivo antitumor efficacy (Amin, et al. AACR 2020).
Here, we report the primary safety/efficacy analysis with PolaGVen
in a Phase 1b/2 study of pts with R/R FL (GO29833; NCT02611323).
Methods: Pts received induction treatment every 21 days (D) x six
cycles (C) of: Pola 1.4–1.8mg/kg intravenously (IV) in dose esca-
lation (DE) or recommended Phase II dose (RP2D) on D1; G
1000mg IV (C1: D1, D8, D15; C2–6: D1); and oral Ven 200–
800mg (DE or RP2D; D1–21). Pts with complete response/partial
response/stable disease (CR/PR/SD) at end of induction (EOI)
received maintenance with G (1000mg on D1 every 2 months [mo]
for 24 mo) and Ven (200–800mg daily) for 8 mo. Primary end-
points were safety/tolerability and positron emission tomography
(PET)CR rate at EOI by independent review committee (IRC) us-
ing modified Lugano criteria.
Results: At the primary analysis (Oct 05, 2020), 74 pts were enrolled.
Median pt age was 64 years (range 36–78); male (57%); Ann Arbor
Stage III–IV (86%); FL International Prognostic Index high risk 3
(55%); bulky disease 7cm (16%); prior lines of therapy 2 (74%);
refractory to: last prior therapy (51%), any prior antiCD20 therapy
(55%), both antiCD20 therapy and an alkylating agent (double re-
fractory; 55%). Grade 3–4 adverse events (AEs) were experienced by
73% of pts; most commonly, neutropenia (39%), thrombocytopenia
(19%), and infections (16%; mainly pneumonia). AEs led to dose
reduction in 38% and interruption in 68% of pts (mainly modifications
to Ven). One fatal AE was reported (pneumonia). In total, 49 pts were
treated at RP2D (Pola 1.8mg/kg +Ven 800mg) and were evaluable
for efficacy. PETCR rate at EOI by IRC was 57% (Table). With a
median followup of 14.4 mo (range 8.2–28.4), the 12mo
progressionfree survival (PFS) was 73% (95% confidence interval:
59.4–86.9). Median PFS was not reached.
Conclusions: The safety profile of PolaGVen is consistent with the
known profiles of the individual drugs. Response rates at EOI with
PolaGVen are encouraging in this R/R FL patient population.
Additional followup is needed to assess PFS benefit during mainte-
nance treatment and beyond.
EA previously submitted to ASCO 2021.
The research was funded by: F. HoffmannLa Roche Ltd/Genentech,
Inc. Third party medical writing assistance, under the direction of the
authors, was provided by Carla Smith, MSc, of Ashfield MedComms,
an Ashfield Health company, and was funded by F. HoffmannLa
Roche Ltd.
Keywords: Indolent nonHodgkin lymphoma, Molecular Targeted
Therapies, Combination Therapies
Conflicts of interests pertinent to the abstract
R. Bannerji
Employment or leadership position: Sanofi Pasteur
Research funding: Abbvie, Genentech, Inc., F. HoffmannLa Roche
Ltd, Regeneron, Abbvie/Pharmacyclics
S. Yuen
Educational grants: Genentech, Inc.
T. Phillips
Consultant or advisory role: ADCT, Genentech, Inc., Abbvie, Phar-
macyclics, Bayer, BMS, Incyte, TG Therapeutics, Gilead, Astra Zeneca
Honoraria: Lymphoma connect
Research funding: Bayer, Abbvie, BMS, Incyte
I. Isufi
Consultant or advisory role: Astra Zeneca, Celgene, Kite, Novartis,
Epizyme
Honoraria: Bayer Taiwan
P. Marlton
Consultant or advisory role: F. HoffmannLa Roche Ltd, AbbVie,
Janssen, Astellas, Gilead, AstraZeneca, BeiGene, Jazz Pahrmaceuticals
Educational grants: F. HoffmannLa Roche Ltd
Other remuneration: Speakers' bureau: AbbVie
TABLE: Responses at EOI by modified Lugano criteria (RP2D; =49)
170
-
SUPPLEMENT ABSTRACTS
J. F Seymour
Consultant or advisory role: Abbvie, Acerta Pharma, Janssen, F.
HoffmannLa Roche Ltd, Sunesis Pharmaceuticals, Takeda, AstraZe-
neca, BristolMyers Squibb, Gilead Sciences, MEI Pharma, MorphoSys
Honoraria: Abbvie, Acerta Pharma, Janssen, F. HoffmannLa Roche
Ltd, Sunesis Pharmaceuticals, Takeda
Research funding: Abbvie, Celgene, Janssen, F. HoffmannLa
Roche Ltd
Educational grants: Abbvie, F. HoffmannLa Roche Ltd
Other remuneration: Speakers' bureau: Abbvie, F. HoffmannLa
Roche Ltd; Expert Testimony: F. HoffmannLa Roche Ltd
P. Corradini
Consultant or advisory role: AbbVie, ADC Therapeutics, Amgen,
Celgene, Daiichi Sankyo, Gilead, Incyte, Janssen, Kite, KyowaKirin,
Novartis, F. HoffmannLa Roche Ltd, Sanofi, Servier, Takeda
Honoraria: AbbVie, ADC Therapeutics, Amgen, Celgene, Daii-
chi Sankyo, Gilead, Incyte, Janssen, Jazz Pharmaceutics, Kite,
KyowaKirin, Novartis, F. HoffmannLa Roche Ltd, Sanofi, Servier,
Takeda
G. Gritti
Consultant or advisory role: Autolus, Gilead, IQvia, Amgen, F.
HoffmannLa Roche Ltd, Takeda
Honoraria: Takeda
Educational grants: F. HoffmannLa Roche Ltd, AbbVie, Gilead,
Janssen, Takeda
J. Hirata
Employment or leadership position: Genentech, Inc.
Stock ownership: F. HoffmannLa Roche Ltd
L. Musick
Employment or leadership position: Genentech, Inc.
Stock ownership: F. HoffmannLa Roche Ltd/GNE
S. Saha
Employment or leadership position: Genentech, Inc.
B. Croft
Employment or leadership position: Genentech, Inc.
Stock ownership: Genentech, Inc./F. HoffmannLa Roche Ltd
C. Flowers
Consultant or advisory role: Abbvie, Bayer, BeiGene, Celgene,
Denovo Biopharma, Genentech/Roche, Gilead, Karyopharm, Phar-
macyclics/Janssen, Spectrum
Research funding: 4D, Abbvie, Acerta, Adaptimmune, Allogene,
Amgen, Bayer, Celgene, Cellectis, EMD, Gilead, Genentech/Roche,
Guardant, Iovance, Janssen Pharmaceutical, Kite, Morphosys, Nektar,
Novartis, Pfizer, Pharmacyclics, Sanofi, Takeda, TG Therapeutics,
Xencor, Ziopharm, Burroughs Wellcome Fund, Eastern Cooperative
Oncology Group, National Cancer Institute, V Foundation, Cancer
Prevention and Research Institute of Texas: CPRIT Scholar in Cancer
Research
112 |CHRONOS3: RANDOMIZED PHASE III STUDY OF
COPANLISIB PLUS RITUXIMAB VS RITUXIMAB/PLACEBO IN
RELAPSED INDOLENT NONHODGKIN LYMPHOMA (INHL)
P. L. Zinzani
1
, M. Capra
2
, M. Özcan
3
, F. Lv
4
, W. Li
5
, E. Yañez
6
, K.
Sapunarova
7
, T. Lin
8
, J. Jin
9
, W. Jurczak
10
, A. Hamed
11
, M.C. Wang
12
,
R. Baker
13
, I. Bondarenko
14
, Q. Zhang
15
, J. Feng
16
, K. Geissler
17
, M.
Lazaroiu
18
, G. Saydam
19
, Á. Szomor
20
, K. Bouabdallah
21
, R. Galiulin
22
,
T. Uchida
23
, L. Mongay Soler
24
, A. Cao
25
, F. Hiemeyer
26
, A. Mehra
27
,
B. H. Childs
28
, Y. Shi
29
, M. J. Matasar
30
1
IRCCS Azienda OspedalieroUniversitaria di Bologna, Istituto di Emato-
logia “Seràgnoli”; Università di Bologna, Dipartimento di Medicina Spe-
cialistica, Diagnostica e Sperimentale, Bologna, Italy,
2
Hospital Mãe de
Deus, Centro de Hematologia e Oncologia, Porto Alegre, Brazil,
3
Ankara
University School of Medicine, Hematology Department, Ankara, Turkey,
4
Fudan University Shanghai Cancer Center, Department of Medical
Oncology, Shanghai, China,
5
The First Hospital of Jilin University,
Department of Hematology, Changchun, China,
6
University of La Fron-
tera, Department of Internal Medicine, OncologyHematology Unit,
Temuco, Chile,
7
Medical University, Department of Internal Medicine,
Hematology Division, Plovdiv, Bulgaria,
8
Sun Yatsen University Cancer
Center, Department of Medical Oncology, Guangzhou, China,
9
The First
Affiliated Hospital of Zhejiang University College of Medicine, Department
of Hematology, Hangzhou, China,
10
Maria SkłodowskaCurie National
Research Institute of Oncology, Department of Clinical Oncology, Krakow,
Poland,
11
Petz Aladár Megyei Oktató Kórház, Hematológiai Osztály, Gyor,
Hungary,
12
Chang Gung Memorial Hospital Kaohsiung, Department of
Medicine, Kaohsiung, Taiwan,
13
Perth Blood Institute, Murdoch Univer-
sity, Western Australia Centre for Thrombosis and Haemostasis, Perth,
Australia,
14
City Dnipropetrovsk Multifield Clinical Hospital, 4 DSMA,
Chemotherapy Department, Dnipro, Ukraine,
15
Harbin Medical Univer-
sity, Cancer Hospital, Department of Medical Oncology, Harbin, China,
16
Jiangsu Cancer Hospital, Department of Medical Oncology, Nanjing,
China,
17
Sigmund Freud University, 5th Medical Department with He-
matology, Oncology and Palliative Medicine, Vienna, Austria,
18
S.C. Poli-
clinica de Diagnostic Rapid S.A., Department of Hematology, Brasov,
Romania,
19
Ege Üniversitesi Tıp Fakültesi, Division of Hematology, Izmir,
Turkey,
20
Pécsi Tudományegyetem Klinikai Központ, 1st Department of
Internal Medicine, Pécs, Hungary,
21
University Hospital of Bordeaux,
Hematology and Cellular Therapy Department, Bordeaux, France,
22
Clinical Oncological Dispensary of Omsk Region, Department of
Chemotherapy for Children and Adults, Omsk, Russian Federation,
23
Japanese Red Cross Nagoya Daini Hospital, Department of Hematology
and Oncology, Nagoya, Japan,
24
Bayer HealthCare Pharmaceuticals, Inc.,
Clinical Development, Whippany, USA,
25
Bayer HealthCare Pharmaceu-
ticals, Inc., Clinical Statistics, Whippany, USA,
26
Pharmaceuticals Division,
Bayer AG, Clinical Statistics, Berlin, Germany,
27
Bayer HealthCare Phar-
maceuticals, Inc., Clinical Development, Whippany, USA,
28
Bayer
HealthCare Pharmaceuticals, Inc., Clinical Development, Whippany, USA,
29
National Cancer Center/National Clinical Research Center for Cancer/
Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union
Medical College, Department of Medical Oncology, Beijing, China,
SUPPLEMENT ABSTRACTS
-
171
30
Memorial Sloan Kettering Cancer Center, Department of Medicine, New
York, USA
Introduction: Rituximab (R)based therapies are standard for pa-
tients (pts) with relapsed advanced iNHL. Copanlisib (C) is a PI3K
inhibitor approved as monotherapy for relapsed follicular lymphoma
(FL) in pts who have had 2 prior systemic therapies. We report
primary data from the Phase III CHRONOS3 study of treatment
with C+Rvs placebo (P)+R in relapsed iNHL (NCT02367040).
Methods: Pts with relapsed iNHL who were progressionfree and
treatmentfree for 12 months (mo) after last Rbased therapy or
unwilling/unfit to receive chemotherapy were randomized 2:1 to
receive C+R or P+R. C 60 mg/P was given i.v. on days 1, 8, and 15
(28day cycle); R 375 mg/m
2
was given i.v. on days 1, 8, 15, and 22
during cycle 1 and on day 1 of cycles 3, 5, 7, and 9. Primary endpoint:
centrally assessed progressionfree survival (PFS). Secondary end-
points: objective response rate (ORR), duration of response, complete
response rate (CRR), overall survival (OS), and treatmentemergent
adverse events (TEAEs). The data cutoff date was August 31, 2020.
Results: 307 pts were randomized to C+R and 151 to P+R. FL was
the most common lymphoma histology subtype (60.0%), followed by
marginal zone (MZL, 20.7%), small lymphocytic (SLL, 10.9%), and
lymphoplasmacytic/Waldenström macroglobulinemia (LPL/WM,
8.3%). Median age was 63 years (range 2891). With a median follow
up of 19.2 mo, the primary study endpoint was met: C+R significantly
reduced the risk of disease progression/death vs P+R (hazard ratio
[HR] 0.52 [95% CI 0.39, 0.69]; 1sided p =0.000002); median PFS
was 21.5 mo (95% CI 17.8, 33.0) vs 13.8 mo (95% CI 10.2, 17.5),
respectively. Reductions in risk of progression/death were seen
across all histology subtypes (HR [95% CI]): FL 0.580 [0.404, 0.833];
MZL 0.475 [0.245, 0.923]; SLL 0.243 [0.111, 0.530]; LPL/WM 0.443
[0.160, 1.231]. ORRs were 80.8% (CRR 33.9%) for C+R and 47.7%
(CRR 14.6%) for P+R. Higher ORRs and CRRs were seen across all
iNHL subtypes with C+R treatment. Median OS was not estimable.
Most common TEAEs (all grades [G]/G3+) in pts receiving C+R were
hyperglycemia (69.4%/56.4%), hypertension (49.2%/39.7% [all G3]),
and diarrhea (33.6%/4.9% [all G3]). For pts receiving P+R, hyper-
glycemia (23.3%/8.2% [all G3]), hypertension (19.2%/8.9% [all G3]),
neutropenia (16.4%/12.3%), and upper respiratory tract infection
(16.4%/0%) were the most common TEAEs. Serious adverse events
were higher with C+R (47.2%) vs P+R (18.5%). G5 TEAEs occurred in
6 pts (2.0%) receiving C+R (1 [0.3%] deemed treatmentrelated;
pneumonitis) and 1 (0.7%) receiving P+R.
Conclusions: C+R demonstrated broad and superior efficacy vs P+R
in pts with relapsed iNHL. The safety profile of C+R was manageable
and consistent with C and R as monotherapy. Copanlisib is the first
PI3K inhibitor to be safely combined with R in relapsed iNHL, rep-
resenting a potential new therapy option for relapsed iNHL across all
subtypes.
EA previously submitted to AACR and EHA 2021.
The research was funded by: Bayer AG, Writing Support was pro-
vided by Complete HealthVizion
Keywords: Indolent nonHodgkin lymphoma, Combination Therapies
Conflicts of interests pertinent to the abstract
P. L. Zinzani
Consultant or advisory role: AbbVie, ADC Therapeutics, Bristol
Myers Squibb, Celgene, Celltrion, EUSA Pharma, Gilead, Immune
Design, Incyte, Janssen, JanssenCilag, Kyowa Kirin, Merck, MSD,
Portola, Roche, Sandoz, Sanofi, Servier, Takeda, TG Therapeutics,
Verastem
Honoraria: AbbVie, ADC Therapeutics, Bristol Myers Squibb, EUSA
Pharma, Gilead, Incyte, Janssen, Kyowa Kirin, Merck, MSD, Roche,
Servier, Takeda, TG Therapeutics, Verastem
Research funding: Portola
M. Özcan
Honoraria: Amgen and Takeda
Research funding: AbbVie, Archigen Biotech, Bayer, Celgene, F.
HoffmannLa Roche Ltd., Janssen, MSD, Takeda
Educational grants: AbbVie, Amgen, Bristol Myers Squibb, F.
HoffmannLa Roche Ltd., Janssen, Takeda
Other remuneration: Abdi İbrahim, Jazz Pharmaceuticals, Sanofi
W. Jurczak
Research funding: Bayer, Gilead, MEI Pharma, TG Therapeutics
R. Baker
Consultant or advisory role: JanssenCilag, Roche
Research funding: AbbVie, Acerta Pharma, Alexion, Amgen, Bayer,
Boehringer Ingelheim, Bristol Myers Squibb, Celgene, CSL Behring,
Daiichi Sankyo, JanssenCilag, MorphoSys AG, Pfizer, Portola, Rigel
Pharmaceuticals, Roche, Sanofi, Takeda, Technoclone
K. Geissler
Consultant or advisory role: Amgen, Celgene, Novartis, Ratiopharm,
Roche
T. Uchida
Other remuneration: Bristol Myers Squibb, Celgene, Chugai Phar-
maceutical, Eisai, Janssen, Kyowa Kirin, Mundipharma, Nippon Shi-
nyaku, Novartis, Ono Pharmaceutical, Otsuka, Pfizer, Takeda
L. Mongay Soler
Employment or leadership position: Bayer HealthCare Pharmaceu-
ticals, Inc.
A. Cao
Employment or leadership position: Bayer HealthCare Pharmaceu-
ticals, Inc.
F. Hiemeyer
Employment or leadership position: Bayer AG
A. Mehra
Employment or leadership position: Bayer HealthCare Pharmaceu-
ticals, Inc.
B. H. Childs
Employment or leadership position: Bayer HealthCare Pharmaceu-
ticals, Inc.
172
-
SUPPLEMENT ABSTRACTS
M. J. Matasar
Consultant or advisory role: Bayer, Daiichi Sankyo, F. HoffmannLa
Roche Ltd., Genentech, Inc., Juno Therapeutics, Merck, Rocket Medi-
cal, Seattle Genetics, Takeda, Teva, ImmunoVaccine Technologies, TG
Therapeutics
Honoraria: Bayer, F. HoffmannLa Roche Ltd., Genentech, Inc.,
GlaxoSmithKline, ImmunoVaccine Technologies, Janssen, Pharmacy-
clics, Seattle Genetics, Takeda, TG Therapeutics
Research funding: Bayer, F. HoffmannLa Roche Ltd., Genentech, Inc.,
GlaxoSmithKline, Janssen, Pharmacyclics, Rocket Medical, Seattle
Genetics, IGM Biosciences
113 |ZANDELISIB, A PI3KδINHIBITOR ON INTERMITTENT
SCHEDULE (IS) IN FOLLICULAR LYMPHOMA PATIENTS WHO
PROGRESSED WITHIN 24 MONTHS OF FIRSTLINE
CHEMOIMUNOTHERAPY (POD24)
J. Pagel
1
, N. Reddy
2
, D. Jagadeesh
3
, A. Stathis
4
, A. S. Asch
5
, H.
Salman
6
, V. P. Kenkre
7
, J. D. Soumerai
8
, J. LlorinSangalang
9
, I. Gor-
batchevsky
10
, J. Li
11
, A. D. Zelenetz
12
1
Swedish Cancer Institute, Hematology and Oncology, Seattle,
Washington, USA,
2
Vanderbilt University Medical Center, Hematology
and Oncology, Nashville, USA,
3
Cleveland Clinic, Hematology and Medical
Oncology, Cleveland, USA,
4
IOSIOncology Institute of Southern
Switzerland, Ospedale Regionale Di Bellinzona E Valli, Oncology, Bellin-
zona, Switzerland,
5
University of Oklahoma Health Sciences Center
Stephenson Cancer Center, Hematology and Oncology, Oklahoma City,
USA,
6
Stony Brook Medical Center, Hematology and Oncology, Stony
Brook, USA,
7
Carbone Cancer Center, Hematology and Oncology, Madi-
son, USA,
8
Massachusetts General Hospital, Hematology and Oncology,
Boston, USA,
9
MEI Pharma, Inc, Clinical Development, San Diego, USA,
10
MEI Pharma, Inc, Clinical Development, San Diego, USA,
11
MEI Pharma,
Inc, Biometrics, San Diego, USA,
12
Memorial Sloan Kettering Cancer
Center, Hematology and Oncology, New York City, USA
Introduction: Follicular lymphoma (FL) patients (pts) with POD24
have poorer survival and may benefit from novel therapies at relapse.
Zandelisib (ME401), a potent, selective, and structurally differenti-
ated oral PI3kδinhibitor was evaluated in a dose escalation/expan-
sion Phase 1b study for FL demonstrating a high objective response
rate (ORR) and well tolerated when given on IS (J Clin Oncol
2020;38: #8016). We report here results based on POD24 status
(NCT02914938)
Methods: Eligible pts had 1 prior therapy, adequate bone marrow
and organ function, ECOG performance status 2, and no prior PI3K
therapy. Zandelisib was administered at 60 mg once daily for 8 weeks
followed by IS on days 17 of each subsequent 28day cycle, either as
monotherapy or with rituximab at 375 mg/m
2
for 8 doses in Cycles 1
6. Treatment was continued until disease progression, intolerance, or
withdrawal of consent. Imaging scans were obtained after 2 and 6
cycles, and then every 6 cycles. Response was reported based on
Lugano criteria.
Results: 37 FL pts were enrolled and received zandelisib on IS as
monotherapy (N =18) or in combination with rituximab (N =19).
Median number of prior therapies =2 (range, 15). The ORR was
86.5% (32/37) with 27% CR (complete response). The ORR and CR
rate were 77.8 % (14/18) and 27.8% in the monotherapy group and
94.7% (18/19) and 26.3% respectively in the rituximab combination
group. Median duration of response (DOR) among all pts was not
reached with a median followup of 16.9 months (mos) (1.233.1+).
22 pts (59%) were POD24, of which 15 (68%) had 2 prior lines of
therapy. Despite more refractory disease, ORR among the POD24
pts was 81.8% (Table). Zandelisib on IS was well tolerated. 3 pts (8%)
discontinued therapy due to an adverse event (AE). Grade (Gr) 3 AE
of special interest (AESI) were 2 (5.4%) diarrhea, 2 (5.4%) colitis, 3
(8.1%) rash, 3 (8.1%) ALT elevation, 1 (2.7%) AST elevation and no
pulmonary infection.
Conclusions: Zandelisib administered on IS as monotherapy or with
rituximab resulted in a highrate of durable responses in FL, both in
POD24 and nonPOD24 groups. Therapy was welltolerated with
low rate of Gr 3 classrelated AESI and discontinuation due to AE's.
Zandelisib as monotherapy is being evaluated in a global Phase 2
study in FL and MZL after failure of 2 prior therapies
(NCT03768505). A Phase 3 study of zandelisib plus rituximab in FL
and MZL after failure of prior immunochemotherapy will begin
enrollment in 2021.
EA previously submitted to ASCO 2021.
The research was funded by: MEI Pharma
Keywords: Molecular Targeted Therapies, Indolent nonHodgkin
lymphoma
Conflicts of interests pertinent to the abstract
J. Pagel
Consultant or advisory role: Gilead Sciences, Actinium Pharmaceu-
ticals, BeiGene, Loxo, Astra Zeneca, MEI Pharma, MorphoSys
SUPPLEMENT ABSTRACTS
-
173
N. Reddy
Honoraria: Celgene, Morphosys
D. Jagadeesh
Consultant or advisory role: Atara Biotherapeutics, Verastem, Kyowa
Kirin
Research funding: Seattle Genetics, Regeneron, MEI Pharma,
Debiopharm Group, Seattle Genetics, Trillium THerapeutics, ADC
Therapeutics, Rhizen Pharmaceuticals
A. Stathis
Consultant or advisory role: Lilly, Bayer,
Research funding: Merck, Pfizer, Roche, Novartis, Bayer, Lilly, ADC
Therapeutics, MEI Pharma, Cellestia Biotech
Educational grants: PharmaMar, Abbvie
A. S. Asch
Research funding: Forty Seven, MEI Pharma, Astellas Pharma, Car-
tesian Therapeutics, MacroGenics, Juno Therapeutics
Other remuneration: provisional Patent submitted: Immediate Family
Member
J. D. Soumerai
Consultant or advisory role: Abbvie, BeiGene, BristolMyers Squibb,
TG Therapeutics
Research funding: Genentech/Roche, BeiGene, TG THerapeutics,
BostonGene, Glaxo SmithKline, Adaptive Biotechnologies
J. LlorinSangalang
Employment or leadership position: Medical DirectorMEI
Pharma
I. Gorbatchevsky
Employment or leadership position: VPClinical Development MEI
Pharma
J. Li
Employment or leadership position: Senior Director: BiometricsMEI
Pharma
A. D. Zelenetz
Consultant or advisory role: Gilead, Amgen, Genetech/Roche, Cel-
gene, DAVOncology, MorphoSys, BeiGene, MEI Pharma, Vaniam
Group, Verastem, Pharmacyclics, Karyopharm, debiopharm, Seattle
Genetics, Quant Health, Kite, curis, Coherus Biosciences, Juno, BMS,
Curio Science
Honoraria: NCCN, Clinical Care Options, PER, Plexus, Oncology In-
formation Group
Research funding: Genentech/Roche, gilead, MEI Pahrma, Beigene
114 |OUTCOMES IN LATERLINES OF THERAPY FOR
RELAPSED/REFRACTORY FOLLICULAR LYMPHOMA: RESULTS
FROM THE INTERNATIONAL SCHOLAR5 STUDY
P. Ghione
1
, H. Ghesquieres
2
, S. Bobillo
3
, A. R. Patel
4
, S. Kanters
5
, K.
Deighton
6
, H. Dong
5
, Y. Yang
4
, L. Ma
4
, E. H. LimbrickOldfield
5
, J.
Thornton Snider
4
, S. W. Wade
7
, M. T. Riberio
8
, A. Sudhindra
4
, J.
Radford
9
, M. L. Palomba
10
, J. Gribben
11
1
Roswell Park Comprehensive Cancer Center and Memorial Sloan
Kettering Cancer Center, Buffalo and New York, New York, USA,
2
Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, Lyon, France,
3
Vall
D’Hebron Insitute of Oncology, Department of Haematology and
Oncology, Barcelona, Spain,
4
Kite, A Gilead Company, Santa Monica, USA,
5
RainCity Analytics, Vancouver, Canada,
6
Delta Hat, Nottingham, UK,
7
Wade Outcomes Research and Consulting, Salt Lake City, Utah, USA,
8
Portuguese Oncology Institute of Porto, Porto, Portugal,
9
The Christie
NHS Foundation Trust and University of Manchester, Manchester, UK,
10
Memorial Sloan Kettering Cancer Center, New York, New York, USA,
11
Cancer Research UK Barts Centre, London, UK
Background: Follicular lymphoma (FL) patients may receive many
lines of treatment (LoTs) to maintain disease control. Current clinical
outcomes in later LoTs (3
rd
) are not well defined. The international
SCHOLAR5 study sought to describe treatment patterns and clinical
outcomes of realworld later LoTs for FL.
Methods: This multicentre retrospective cohort was conducted at
major lymphoma centres in the US and Europe. Adult (18) patients
diagnosed with grade 13a FL, initiating (after 7/2014) a new treat-
ment post 2 previous LoTs were enrolled. Radiotherapy or anti
CD20 therapy alone were not considered prior LoTs. Patients that
transformed before index date were excluded. Objective response
rate (ORR), complete response (CR), progression free survival (PFS)
and overall survival (OS) were analysed by LoT. Timetoevent out-
comes were determined by KaplanMeier. A subgroup analysis was
conducted among 3
rd
LOT patients who progressed within 24 months
of initiating firstline chemoimmunotherapy (POD24).
TABLE 1: Outcome Results
174
-
SUPPLEMENT ABSTRACTS
Results: Data from 184 patients were extracted, of whom 123 fulfilled
the inclusion criteria. Of the 123, 99 initiated a 3
rd
LoT, 54 initiated a
4
th
LoT, and 27 initiated 5
th
LoTs. Proportions with highrisk attri-
butes included 31% with POD24, 43% with refractory disease and 44%
with stage 3 or higher at the start of their first eligible (3) LoT. Median
time from initial diagnosis to initiation of 3
rd
LoT was 84 months overall
and 44 months in the POD24 patients. The most commonly used
regimen in 3
rd
LoT (37%) was chemoimmunotherapy; in 4
th
LoT were
experimental drugbased (33%) or chemoimmunotherapy (33%); and
in 5
th
LoT was chemoimmunotherapy (28%). ORR at 3
rd
LoT was 67%
(CR 42%), decreasing after each subsequent LoT. OS and PFS at 18
months after 3
rd
LoT were 84% and 35% respectively but decreased to
40% and 3% in 5th LoTs. In subgroup analysis, the POD24 group had
much lower median and 18month PFS at 3
rd
LoT compared with the
nonPOD24 group (Table 1).
Conclusions: Even after excluding cases of transformation, FL patients
respond less and for shorter time to treatment after each LoT. Addi-
tionally, PFS decreases dramatically among POD24 patients. These
findings demonstrate an unmet need in laterline FL. Data from addi-
tional subjects are being collected and analysis will be updated for the
meeting.
The research was funded by: Kite, a Gilead Company
Keywords: Indolent nonHodgkin lymphoma
Conflicts of interests pertinent to the abstract
H. Ghesquieres
Consultant or advisory role: Gilead Sciences, Celgene, Roche
Honoraria: Gilead, Janssen, Celgene
Educational grants: Roche, Gilead Sciences, Celgene, Takeda
S. Bobillo
Consultant or advisory role: ROCHE
Educational grants: ROCHE
Other remuneration: Speaker's bureau: ROCHE, GILEAD
A. R. Patel
Employment or leadership position: Kite, A Gilead company
Stock ownership: Kite, A Gilead company
S. Kanters
Employment or leadership position: RainCity Analytics
Research funding: RainCity Analytics has received funds from for
profit healthcare companies for research
K. Deighton
Employment or leadership position: Delta Hat
H. Dong
Employment or leadership position: Kite, A Gilead company
Stock ownership: Kite, A Gilead company
Y. Yang
Employment or leadership position: Kite, A Gilead Company
L. Ma
Employment or leadership position: Kite, A Gilead Company
E. H. LimbrickOldfield
Employment or leadership position: RainCity Analytics
J. Thornton Snider
Employment or leadership position: Kite, A Gilead Company
Stock ownership: Gilead Sciences
Research funding: Previously employed at PrecisionHEOR, which
receives research funding from life sciences companies.
S. W. Wade
Consultant or advisory role: Kite Pharma, Amgen, Allergan
A. Sudhindra
Employment or leadership position: Atara Biotherapeutics, Kite
Pharma
Stock ownership: Atara Biotherapeutics, Gilead
J. Radford
Consultant or advisory role: Takeda/ADCT/BMS/Novartis/
KitePharma
Stock ownership: ADCT & AZ (spouse)
Honoraria: akeda/ADCT/BMS/Novartis/KitePharma
Other remuneration: Speaker's bureau and expert testimony:
Takeda/ADCT
M. L. Palomba
Consultant or advisory role: Novartis, Kite, PCYC, BeiGene
Stock ownership: Seres, Notch
Research funding: Seres
Other remuneration: Patents, royalties. other IP: Juno, Seres, Wol-
ters Kluwer
J. Gribben
Consultant or advisory role: AZ
Research funding: Janssen, AZ
115 |OUTCOME OF 133 PATIENTS WITH FOLLICULAR
LYMPHOMA (FL) PROGRESSING BEFORE 24 MONTHS (POD24)
AFTER IMMUNOCHEMOTHERAPY: A GELTAMO STUDY
A. Muntañola
1
, L. Magnano
2
, S. Mercadal
3
, M. Huguet
4
, S. Bobillo
5
, M.
BastosOreiro
6
, A. JiménezUbieto
7
, J. Rovira
8
, A. Rivero
2
,
M. Alcoceba
9
, P. Mozas
2
, L. Luizaga
10
, S. AlonsoÁlvarez
11
, A. Rivas
Delgado
2
, E. Giné
2
, D. Caballero
12
, J. M. Sancho
4
, A. LópezGuillermo
2
1
Hospital Universitari Mútua Terrassa, Hematology, Barcelona, Spain,
2
Hospital Clínic Barcelona, Hematology, Barcelona, Spain,
3
Hospital
Duran Reynals ICO Hospitalet, Hematology, Barcelona, Spain,
4
Hospital
Germans Trias i Pujol ICO Badalona, Hematology, Barcelona, Spain,
5
Hospital Vall d'Hebron, Hematology, Barcelona, Spain,
6
Hospital
Universitario Gregorio Marañón, Hematology, Madrid, Spain,
7
Hospital
Universitario 12 de Octubre, Hematology, Madrid, Spain,
8
Hospital
Universitari Joan XXIII ICO Tarragona, Hematology, Tarragona, Spain,
9
Hospital Universitario de Salamanca, Molecular Biology, Salamanca,
Spain,
10
Hospital Universitari Mútua Terrassa, Pathology, Barcelona,
Spain,
11
Hospital Universitario Central de Asturias, Hematology, Oviedo,
SUPPLEMENT ABSTRACTS
-
175
Spain,
12
Complejo Asistencial Universitario de Salamanca /IBSAL,
Hematology, Salamanca, Spain
Introduction: Patients with FL have prolonged survival, but with a
clinical course of successive relapses. Patients progressing before 24
months (POD24) have been identified as a poor prognosis subset
with 5year survival about 50%. Nevertheless, this group is hetero-
geneous with some cases showing notable survival after 1
st
relapse/
progression. The aim of this study was to characterize POD24 FL
population and to identify main prognostic factors at progression.
Patients and methods: 133 patients (66M/67F; median age at first
relapse 58 years) diagnosed with grades 13a FL in 9 GELTAMO
centers, treated with immunochemotherapy (71% RCHOP), plus
maintenance with rituximab in 42 (32%), who have progressed before
24 months from starting therapy were the subjects of the present
study. Cases showing histological transformation at progression/
relapse were not included.
Results: Main clinical features at time of progression were the
following: advanced stage, 75%; bone marrow involvement, 26%; four
or more nodal areas, 52%; high serum LDH and beta2microglobulin,
33% and 31%, respectively. Distribution by FLIPI was: lowrisk 26%,
intermediaterisk 29%, highrisk 45%. Salvage treatment consisted in
immunochemotherapy (ESHAP regimen in most cases) in 39% of cases,
purine analogs in 38% and other in 23%. Response was assessable in
108 cases, with a proportion of CR and PR of 51% and 30%, respec-
tively. 21 patients (16%) in response received intensification with
ASCT at this point. 10year progressionfree survival from salvage was
26% (95%CI 1834%). After a median followup of 11.5 years, 75 pa-
tients have died, with a 10year survival from POD24 (SFPOD24) of
43% (95%CI: 3452%) (figure A). Variables at the time of relapse pre-
dicting poor survival were the following: age >60 years (p <0.001),
high LDH (p <0.001), Hb <12 g/dL (p <0.001), advanced AnnArbor
stage (p <0.001), higherrisk FLIPI (p <0.001) (figure B). As ex-
pected, patients reaching CR after salvage showed better SFPOD24
than the other groups (figure C). However, patients in response in
whom ASCT was performed did not have better SFPOD24 than those
responding cases managed without transplant. In the multivariate
analysis only FLIPI score at relapse (low/intermediate vs. high, p =
0.040; HR 0.51) and response to salvage therapy (CR vs. PR/NR, p <
0.001; HR 0.15) maintained prognostic significance for SFPOD24.
Conclusion: Although overall the outcome of POD24 FL patients is
poor, a considerable group of them, i.e., lowintermediate FLIPI
and those reaching CR after salvage, still have a favorable
prognosis.
Keywords: Diagnostic and Prognostic Biomarkers, Indolent non
Hodgkin lymphoma
No conflicts of interest pertinent to the abstract.
116 |BENDAMUSTINERITUXIMAB COMPARED TO
RITUXIMABCHOP/CVP FOR TREATMENT OF PATIENTS WITH
INDOLENT LYMPHOMA IN ONTARIO: A POPULATIONBASED
STUDY
A. Suleman
1
, S. Aktar
2
, N. Liu
2
, K. Chan
3
, M. Cheung
3
, A. Prica
4
1
University of Toronto, Department of Medicine, Toronto, Canada,
2
Institute for Clinical Evaluative Sciences, (ICES), Toronto, Canada,
3
Sunnybrook Health Sciences Centre, Odette Cancer Centre, Toronto,
Canada,
4
Princess Margaret Cancer Centre, Cancer Clinical Research Unit,
Toronto, Canada
Introduction: For patients with symptomatic advanced stage indolent
lymphoma, rituximab (R) was traditionally used alongside cyclo-
phosphamide, vincristine, prednisone (CVP), or cyclophosphamide,
doxorubicin, vincristine, and prednisone (CHOP). Bendamustine plus
rituximab (BR) has been found to increase progressionfree survival
compared to RCHOP/CVP, although controversy exists around its
toxicity profile. Since 2013, bendamustine has been approved for
universal public reimbursement for this indication in Ontario, Can-
ada, and become the preferred regimen. We examined survival and
toxicity of patients with indolent lymphoma treated with BR
compared with RCVP/CHOP in Ontario.
Methods: We conducted a retrospective cohort populationbased
study using administrative healthcare databases from Ontario, Can-
ada. Patients with a diagnosis of indolent lymphoma, excluding
mantle cell lymphoma, who were treated with RCVP/CHOP from
2005 to 2012 or with BR from 20132018 were included. The two
treatment groups were propensity score matched based on lym-
phoma subtype, age, sex, prior cancer diagnosis, time since diagnosis
and rural/urban residence. The primary outcome of the study is
overall survival (OS) from time of first treatment to date of death or
end of study period. Secondary outcomes include toxicities, such as
infections and secondary malignancies, associated resource use, and
outcomes of patients treated with rituximab maintenance therapy.
176
-
SUPPLEMENT ABSTRACTS
Results: A propensitymatched cohort of 2029 patients treated with
BR and 2029 patients treated with RCVP/CHOP were included. The
median age of patients was 64 years and 48% were female in the
cohort. A majority of patients had a diagnosis of follicular lymphoma
(59.3% of patients treated with BR, 59.7% of patients treated with
RCVP/CHOP, p =0.88). Median followup time was 41 and 87
months for patients treated with BR and RCVP/CHOP, respectively.
In this wellmatched cohort, BR was associated with a significant
improvement in survival compared to RCVP/CHOP (HR 0.76, 95%
CI 0.670.88, p <0.01). Fiveyear OS was 80% and 75% for patients
treated with BR and RCVP/CHOP, respectively (Figure 1). A total of
974 patients died during the followup period (331 treated with BR,
643 treated with RCVP/CHOP), of which 875 had causes of death
available. A majority of patients in both groups died from lymphoma
(63.2% treated with BR, 66.4% treated with RCVP/CHOP). Death
from secondary malignancies was less common (11.8% treated with
BR, 12.8% treated with RCVP/CHOP). Few patients died from
infection (6.2% treated with BR, 3.2% treated with RCVP/CHOP).
Conclusions: Our study demonstrates improved OS with BR
compared to RCVP/CHOP for patients with previously untreated
indolent lymphoma. Cause of death in both cohorts was most
frequently attributable to lymphoma. This supports BR as the stan-
dard of care for treatment of symptomatic indolent lymphoma.
The research was funded by: This project was in part supported by
the American Society of Hematology HONORS (Hematology Op-
portunities for the Next Generation of Research Scientists) Award
granted to Adam Suleman.
Keywords: Indolent nonHodgkin lymphoma, Combination Therapies
No conflicts of interest pertinent to the abstract.
117 |MAINTENANCE THERAPY AFTER RBENDAMUSTINE VS
RCHOP IN FIRSTLINE TREATMENT OF LOWGRADE
FOLLICULAR LYMPHOMA: A MULTICENTRE, RETROSPECTIVE
GELTAMO STUDY
M. BastosOreiro
1
, A. Gutierrez
2
, R. Martín
1
, A. Cabero
3
, B. Navarro
4
,
A. JimenezUnieto
5
, C. Alonso
6
, S. Gonzalez de Villambrosia
7
, R.
Córdoba
8
, J. Perez de Oteyza
9
, María Infante
10
, R. Del Campo
11
, A.
De la Fuente
12
, R. Oña
12
, D. García Belmonte
13
, A. Salar
14
, J. M.
Sancho
15
1
Hospital Universitario Gregorio Marañón, Hematology, Madrid, Spain,
2
Hospital Universitario Son Espases, Hematology, Palma de Mallorca,
Spain,
3
Hospital Clínico Universitario de Salamanca, Hematology,
Salamanca, Spain,
4
Hospital Universitario Puerta de hierro, Hematology,
FIGURE 1 KaplanMeier plot of overall survival of the treatment groups from time of treatment initiation
TABLE 1: General Characteristics of the patients and lymphoma at
diagnosis
SUPPLEMENT ABSTRACTS
-
177
Majadahonda, Spain,
5
Hospital Universitario 12 de Octubre, Hematology,
Madrid, Spain,
6
Hospital Arnau de Villanova, Hematology, Valencia, Spain,
7
Hospital Universitario de Valdecillas, Hematology, Santander, Spain,
8
Hospital Universitario Fundación Jiménez Díaz, Hematology, Madrid,
Spain,
9
Hospital Universitario Madrid Sanchinarro, Hematology, Madrid,
Spain,
10
Hospital Infanta Leonor, Hematology, Madrid, Spain,
11
Hospital
Universitario Son LLatzer, Hematology, Palma de Mallorca, Spain,
12
Hospital MD Anderson Madrid, Hematology, Madrid, Spain,
13
Hospital
de la Zarzuela, Hematology, Madrid, Spain,
14
Hospital Universitario del
mar, Hematology, Barcelona, Spain,
15
Hospital Germans Trias i Pujol,
Hematology, Barcelona, Spain
Introduction: After Rituximab (R) plus cyclophosphamide, doxorubicin,
and prednisone (RCHOP) induction therapy (IT), the use of R as
maintenance has improved the outcome of patients with follicular
lymphoma (FL). R plus Bendamustine (RB) has demonstrated excellent
efficacy in this setting, but the role of maintenance (MT) is not clear.
Therefore, we compared both Rbased regimens with R maintenance
for untreated advancedstage follicular FL and compared their
outcomes.
Methods: We retrospectively assessed patients with FL from 16
different GELTAMO centres, treated with either RB or RCHOP as
first line therapy followed by maintenance with R. The outcome and
toxicity were evaluated.
Results: A total of 309 patients with FL were included, 93 in the group
that received RB and 216 in the group that received RCHOP. Pa-
tient's characteristics are resumed in Table 1. RB group was older and
Grade 3A significantly received more RCHOP. All patients completed
induction therapy. GCSF prophylaxis and cytopenias during IT were
more frequent with RCHOP (Table 1), infections rates were similar (R
B 22 [24,2%] vs RCHOP 51 [25,4%], p =0.8). Seventy patients (73%) in
the RB group and 193 (88%) in the RCHOP group completed MT.
Discontinuation was more frequent in RB group, the most common
reasons were cytopenias and infections (Table 2s). Infection related
TABLE 2: Treatment Characteristics and complications
178
-
SUPPLEMENT ABSTRACTS
deaths were more frequent in the RB group (40% vs 7%, p =0.051).
We didn’t find differences in 2
nd
neoplasms.
Complete response at the end of IT and progression rates were
similar in both groups (87% in RB, 90% in RCHOP, and 7.8% in RB
6.3% in RCHOP respectively). Relapses were more frequent in R
CHOP (8% in RB, 21.8% in RCHOP, p =0.019). POD 24 was
similar for both groups (9 [10%] for RB and 21 [10%] for RCHOP).
After a median followup of 6.2 years (5,1 for RB and 6,5 for R
CHOP), 5year rate of progressionfree survival was 84% for RB
vs.75% for RCHOP, (95% confidence interval [CI], 0,79 to 2,6; p =
0.2). (Figure 1) and overall survival, 87% for RB vs. 91% for RCHOP,
(95% [CI], 0.21 to 1.52; p =0.3).
Conclusion: In this series, RCHOP and Rbendamustine showed
similar efficacy in untreatead advancedstage FL. However, mainte-
nance after RB was associated with more toxicity, especially neu-
tropenia and infections.
Keywords: Indolent nonHodgkin lymphoma, Immunotherapy
No conflicts of interest pertinent to the abstract.
118 |OBINUTUZUMAB CAN BE ADMINISTERED AS A 90
MINUTE SHORTDURATION INFUSION (SDI) IN PATIENTS WITH
PREVIOUSLY UNTREATED FOLLICULAR LYMPHOMA: GAZELLE
END OF INDUCTION ANALYSIS
K. Hübel
1
, T. A. Buchholz
2
, K. Izutsu
3
, T. Ishikawa
4
, L. M. Fogliatto
5
, E.
Vorozheikina
6
, D. Klingbiel
7
, S. Pokala
8
, M. Tomiczek
9
, J. Parreira
10
,
M. A. Canales
11
1
Uniklinik Köln, Department of Internal Medicine 1, Köln, Germany,
2
Scripps MD Anderson Cancer Center, San Diego, USA,
3
National Cancer
Center Hospital, Department of Hematology, Tokyo, Japan,
4
Kobe City
Medical Center, General Hospital, Department of Hematology, Hyogo,
Japan,
5
Hospital de Clínicas de Porto Alegre, Department of Hematology,
Porto Alegre, Brazil,
6
IQVIA, Medical and Scientific Services, Moscow,
Russian Federation,
7
F. HoffmannLa Roche Ltd, Product Development
Biometrics, Basel, Switzerland,
8
F. HoffmannLa Roche Ltd, Product
Development Safety, Basel, Switzerland,
9
F. HoffmannLa Roche Ltd,
Product Development Clinical Operations, Basel, Switzerland,
10
F.
HoffmannLa Roche Ltd, Product Development Medical Affairs, Basel,
Switzerland,
11
Hospital Universitario La Paz, Department of Hematology,
Madrid, Spain
Introduction: Obinutuzumab (G)chemotherapy has demonstrated
improved PFS compared with rituximab (R)chemotherapy in previ-
ously untreated advanced follicular lymphoma (FL). G is currently
administered by IV infusion over 3–4 hrs. G SDI from Cycle (C) 2
onwards could be advantageous for pts and infusion facilities. We
report the end of induction (EOI) analysis of the Phase IV GAZELLE
study (NCT03817853), which evaluated a 90minute (min) G SDI in
pts with FL.
Methods: Pts with previously untreated FL who met GELF criteria
received G (1000mg) IV on Day (D) 1, 8 and 15 of C1, and on D1
thereafter, plus chemotherapy (bendamustine, CHOP or CVP) for 6–8
cycles. In C1, pts received G at the standard infusion rate. Pts without
a Grade (Gr) 3 infusionrelated reaction (IRR) in C1 received G as a
FIGURE 1 Progressionfree survival and Overall survival comparing RB and RCHOP
TABLE: SDI duration during induction
C1
SDI duration D1 D8 15 C2 C3 C4 C5 C6 C7 C8
Median duration, mins
(minmax)
269.5 (115
1630)
210.0 (82
357)
205.0 (80
335)
98.0 (53
193)
95.0 (66
750)
96.0 (88
195)
95.5 (75
245)
96.0 (89
183)
95.0 (63
160)
95.0 (88
105)
Duration 110 mins,
n (%)
0/ 4/ 2/ 106/ 105/ 102/ 101/ 98/ 51/ 52/
113 112 (3.6) 111 (1.8) 110 (96.4) 108 (97.2) 108 (94.4) 107 (94.4) 105 (93.3) 55 (92.7) 52 (100)
SUPPLEMENT ABSTRACTS
-
179
90min SDI from C2 onwards. Pts with a Gr 3 IRR in C1 received G at
the standard infusion rate in C2, and received G SDI from C3 onwards
if no Gr 3 IRR occurred. Pts with a second Gr 3 IRR discontinued G.
At EOI, responding pts received maintenance G (1000mg) as SDI for 2
yrs or until PD. The primary endpoint was incidence of Gr 3 IRR
during C2. IRR was defined as any event occurring during or within 24
hrs of infusion and judged related to treatment.
Results: As of December 3, 2020, 113 pts had completed EOI
treatment. Median age was 62.0 yrs, 50.4% were male, 61.9% had
stage IV FL and 45.1% were classified as highrisk FLIPI. Of the
110 pts who received G SDI in C2, none experienced a Gr 3 IRR.
One patient experienced a Gr 3 IRR with SDI in C5 (hypertension).
All other IRRs with SDI were Gr 1/2. Median SDI duration in C2–8
was 95–98 mins, and SDI duration was 110 mins in >90% of pts
(Table). From C1 onwards, AEs were reported in 99.1% (112/113)
of pts. Gr 3 AEs were observed in 72.6%. Common Gr 3 AEs
(>5%) were neutropenia (50.4%), leukopenia (11.5%), lymphopenia
(10.6%), thrombocytopenia (7.1%), IRR (6.2%) and febrile neu-
tropenia (5.3%). Gr 5 (fatal) AEs were reported in 2 pts (cardiac
arrest and aspiration pneumonia; both considered unrelated to
treatment). CTimaging at EOI demonstrated that: 76/113 (67.3%)
pts had a CR; 22 (19.5%) had a PR; and six (5.3%) had PD; 9 pts
had no response assessment.
Conclusions: In GAZELLE, G SDI from C2 onwards appeared to be
safe. No Gr 3 IRRs were observed in C2 and only one Gr 3 IRR was
reported in subsequent cycles. No new safety signals were reported
and response data were in line with previous studies. SDI time was
110 mins in >90% of pts. G SDI is likely to improve convenience for
pts and efficiency for infusion facilities.
The research was funded by: GAZELLE is sponsored by F. Hoffmann
La Roche Ltd (NCT03817853).
Keywords: Indolent nonHodgkin lymphoma
Conflicts of interests pertinent to the abstract
K. Hübel
Consultant or advisory role: F. HoffmannLa Roche Ltd, Gilead, Hexal,
EUSA
Research funding: F. HoffmannLa Roche Ltd, Celgene, Hexal,
Janssen
Educational grants: F. HoffmannLa Roche Ltd, Celgene, Hexal
Other remuneration: Speakers' bureau F. HoffmannLa Roche Ltd,
Celgene, EUSA
T. A. Buchholz
Employment or leadership position: Scripps Health Care System,
Nucleix, Empyrean Medical Systems
Consultant or advisory role: Genentech, Inc., F. HoffmannLa Roche Ltd
Stock ownership: Nucleix, Empyrean Medical Systems
Honoraria: Genentech, Inc., F. HoffmannLa Roche Ltd, Abivax,
Precisa
Educational grants: Genentech, Inc.
Other remuneration: MD Anderson Cancer Center
K. Izutsu
Honoraria: Chugai Pharmaceutical
Research funding: Chugai Pharmaceutical
E. Vorozheikina
Employment or leadership position: IQVIA, Associate medical director
D. Klingbiel
Employment or leadership position: F. HoffmannLa Roche Ltd
Stock ownership: F. HoffmannLa Roche Ltd
M. Tomiczek
Employment or leadership position: F. HoffmannLa Roche Ltd
J. Parreira
Employment or leadership position: F. HoffmannLa Roche Ltd
Stock ownership: F. HoffmannLa Roche Ltd
Honoraria: F. HoffmannLa Roche Ltd
M. A. Canales
Consultant or advisory role: Astellas, Eusa Pharma, Celgene, Gilead,
Janssen, Karyopharm, Novartis, F. HoffmannLa Roche Ltd, Takeda
Honoraria: Amgen, Gilead, Janssen, F. HoffmannLa Roche Ltd,
Takeda
Educational grants: Gilead, Janssen, Novartis, F. HoffmannLa Roche
Ltd
119 |UPDATED RESULTS OF THE FIL “MIRO” STUDY, A
MULTICENTER PHASE II TRIAL COMBINING LOCAL
RADIOTHERAPY AND MRDDRIVEN IMMUNOTHERAPY IN
EARLYSTAGE FOLLICULAR LYMPHOMA
A. Pulsoni
1
, M. E. Tosti
2
, S. Ferrero
3
, S. Luminari
4
, A. Dondi
5
, A. M.
Liberati
6
, N. Cenfra
7
, D. Renzi
8
, M. Zanni
9
, C. Boccomini
10
, A. J.
Ferreri
11
, S. Rattotti
12
, V. R. Zilioli
13
, P. Bernuzzi
14
, S. Bolis
15
, G.
Musuraca
16
, L. Nassi
17
, T. Perrone
18
, C. Stelitano
19
, A. Anastasia
20
, P.
Corradini
21
, G. Partesotti
22
, F. Re
23
, E. Cencini
24
, C. Mannarella
25
, D.
Mannina
26
, A. L. Molinari
27
, M. Tani
28
, G. Annechini
1
, G. M. Assanto
1
,
L. Grapulin
29
, A. Guarini
30
, M. Cavalli
1
, L. A. De Novi
1
, E. Ciabatti
31
, B.
Mantoan
32
, I. Della Starza
1
, L. Arcaini
33
, U. Ricardi
34
, V. Gattei
35
, S.
Galimberti
36
, M. Ladetto
37
, R. Foà
1
, I. Del Giudice
1
1
Hematology, Sapienza University, Department of Translational and
Precision Medicine, Roma, Italy,
2
Istituto Superiore di Sanità, National
Center for Global Health, Roma, Italy,
3
Hematology Division, University of
Torino/AOU "Città della Salute e della Scienza di Torino", Department of
Molecular Biotechnologies and Health Sciences, Torino, Italy,
4
Hematology
Unit, Arcispedale S. Maria Nuova, Azienda Unità Sanitaria Locale IRCCS,
University of Modena and Reggio Emilia, Reggio Emilia, Italy,
5
Fondazione
Italiana Linfomi Onlus, (FIL), Modena, Italy,
6
A.O. Santa Maria Terni,
University of Perugia, Perugia, Italy,
7
Hematology Unit, S. Maria Goretti
Hospital , AUSL Latina, Latina, Italy,
8
Hematology and Stem Cells
Transplantation Unit, IRCCS Istituto Nazionale dei Tumori Regina Elena,
Roma, Italy,
9
Division of Hematology, SS. Antonio e Biagio Hospital,
Alessandria, Italy,
10
Hematology Department, Città della Salute e della
180
-
SUPPLEMENT ABSTRACTS
Scienza, Torino, Italy,
11
Lymphoma Unit, IRCCS San Raffaele Scientific
Institute, Department of OncoHaematology, Milano, Italy,
12
Division of
Hematology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy,
13
Di-
vision of Hematology, ASST Grande Ospedale Metropolitano Niguarda,
Milano, Italy,
14
Hematology Unit, Guglielmo da Saliceto Hospital, Depart-
ment of OncoHematology, Piacenza, Italy,
15
Hematology Department,
ASST San Gerardo University Hospital, Monza, Italy,
16
Hematology Unit,
IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”,
Meldola (FC), Italy,
17
Division of Hematology, University of Eastern Pied-
mont, Department of Translational Medicine, Novara, Italy,
18
Unit of He-
matology with Transplantation, University of Bari, Dept. of Emergency and
Organ Transplantation, Bari, Italy,
19
Department of Haematology, Azienda
Ospedaliera Bianchi Melacrino Morelli, Reggio Calabria, Italy,
20
Hematol-
ogy, ASST Spedali Civili di Brescia, Brescia, Italy,
21
Division of Hematology,
Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milano, Italy,
22
OncoHematology Department, Nuovo ospedale civile of Sassuolo, Sas-
suolo, Italy,
23
Hematology Clinic, A.O.U. di Parma, Parma, Italy,
24
Unit of
Hematology, Azienda Ospedaliera Universitaria Senese & University of
Siena, Siena, Italy,
25
Hematology Unit, "Madonna delle Grazie" Hospital,
Matera, Italy,
26
Department of Hematology, Azienda Ospedaliera Papardo,
Messina, Italy,
27
Hematology, Ospedale degli Infermi, Rimini, Italy,
28
He-
matology Unit, Santa Maria delle Croci Hospital, Ravenna, Italy,
29
Depart-
ment of Radiotherapy, Policlinico Umberto I, Sapienza University, Roma,
Italy,
30
Hematology, Sapienza University, Department of Molecular Medi-
cine, Roma, Italy,
31
Section of Hematology, University of Pisa, Department
of Clinical and Experimental Medicine, Pisa, Italy,
32
Hematology Division,
University of Torino, Department of Molecular Biotechnologies and Health
Sciences, Torino, Italy,
33
Division of Hematology, Fondazione IRCCS Poli-
clinico San Matteo, University of Pavia, Department of Molecular Medicine,
Pavia, Italy,
34
Radiation Oncology, University of Turin, Department of
Oncology, Torino, Italy,
35
Clinical and Experimental OncoHematology Unit,
CRO Aviano National Cancer Institute, Aviano, Italy,
36
Section of Hema-
tology, University of Pisa, Department of Clinical and Experimental Medi-
cine, Pisa, Italy,
37
Hematology, Az Ospedaliera Santi Antonio e Biagio e
Cesare Arrigo, Università del Piemonte Orientale, Alessandria, Italy
Background: Earlystage follicular lymphoma (FL) is usually managed
with involved field radiotherapy (IFRT), allowing a complete and long
lasting eradication of the disease only in 4050% of patients (pts). The
aim of this multicenter phase II prospective study was to evaluate the
role of MRD in identifying pts unlikely to be cured by IFRT, for whom
an immunotherapy consolidation could improve outcome.
Methods: 110 pts with stage I/II FL were enrolled and treated with
24 Gy IFRT. Peripheral blood (PB) and bone marrow (BM) samples
were centralized to the FIL (Fondazione Italiani Linfomi) MRD
Network of EuroMRDcertified laboratories. In BCL2/IGH+pts at
baseline by both nested PCR (NEST) and RQPCR (RQ) in BM a/o PB,
MRD was analyzed after IFRT and every 6 months over a 3year
period. Pts with MRD+by both NEST and RQ in BM a/o PB after
IFRT or who became MRD+during the followup were treated with 8
weekly doses of the antiCD20 MoAb ofatumumab (OFA). The pri-
mary objective of the study was to define the efficacy of immuno-
therapy in obtaining a negative MRD.
Results: Of the 106 evaluable pts, 50 were males. Median age was 55
y (2983). The FLIPI score was 0 in 59% of pts, 1 in 35%, 2 in 6%. 68%
of pts had inguinal site involvement. At baseline, 30% of pts had a
BCL2/IGH rearrangement (30 MBR, 1 MBR and mcr, 1 mcr) in BM a/
o PB; the concordance between compartments was 90%. All but one
pt achieved a clinical response after IFRT; one additional pt died soon
after IFRT of unrelated causes. MRD evaluation after IFRT revealed
the persistence of BCL2/IGH+cells in PB a/o BM in 60% of pts. MRD
+pts, either after IFRT (n =18) or in case of conversion to MRD+
during the followup (n =6), received OFA, obtaining a conversion to
MRDin 22/24 pts (91.7% CI 73.099.0), significantly superior to
the expected 50% (Fig). After a median FU of 38 m, 17 pts who
achieved a MRDwith OFA are still negative; 5 converted to MRD+
(2 received OFA retreatment, achieving a second MRD; 2 pts were
not retreated due to SarsCov2 pandemic; 1 relapsed). A clinical
relapse or progression was observed in 23 pts: 18 (24.6%) among the
73 “no marker” pts and 5 (15.6%) among the 32 BCL2/IGH+at
baseline (p =0.3), with no significant difference in PFS (p =0.25).
Two early relapses were observed among the 12 pts who became
MRDafter IFRT and 3 among the 24 treated at least once with OFA
(1 MRD+, 1 MRD, 1 converted from MRDto MRD+). Only 1 Pt
relapsed while MRDafter OFA.
Conclusions: MRD data indicate that RT alone is often insufficient to
eradicate the disease, inducing a MRDonly in 40% of pts, notably
longlasting only in half of them. The primary objective of this study
MRD conversion after immunotherapy was largely achieved. The
strategy of an immunotherapy consolidation after IFRT in MRD+pts
allowed increasing molecular responses. However, this strategy is
applicable only to 30% of enrolled pts. A clinical advantage of the
MRD driven treatment strategy is suggested although not significant.
Keywords: Molecular Targeted Therapies, Immunotherapy
Conflicts of interests pertinent to the abstract
A. Pulsoni
Consultant or advisory role: Roche, Merk, Pfyzer, Sandoz;Gylead,
Bristol Meyer Squibb
SUPPLEMENT ABSTRACTS
-
181
A. J. Ferreri
Consultant or advisory role: Adienne, Gilead, Novartis, Juno,
PletixaPharm
Research funding: BMS, Beigene, Pharmacyclics, Hutchison Medi-
pharma, Amgen, Genmab, ADC Therapeutics, Gilead, Novartis, and
Pfizer
V. R. Zilioli
Consultant or advisory role: Roche, Takeda, MSD
Honoraria: Gentili, Gilead
Educational grants: Janssen
120 |CLINICAL OUTCOMES AND THE ROLE OF OBSERVATION
IN EARLYSTAGE FOLLICULAR LYMPHOMA
F. Sha
1
, M. Okwali
1
, A. Alperovich
1
, P. C. Caron
1
, L. Falchi
1
, A.
Hamilton
1
, P. A. Hamlin
1
, S. M. Horwitz
1
, E. Joffe
1
, A. Kumar
1
, M. J.
Matasar
1
, A. J. Moskowitz
1
, A. Noy
1
, C. Owens
1
, L. M. Palomba
1
, I.
RodriguezRivera
1
, D. Straus
1
, G. von Keudell
1
, A. D. Zelenetz
1
, J.
Yahalom
2
, A. Dogan
3
, H. Schoder
4
, V. E. Seshan
5
, G. Salles
1
, A.
Younes
6
, C. L. Batlevi
1
1
Memorial Sloan Kettering Cancer Center, Medicine, New York, USA,
2
Memorial Sloan Kettering Cancer Center, Radiation Oncology, New York,
New York, USA,
3
Memorial Sloan Kettering Cancer Center, Pathology,
New York, New York, USA,
4
Memorial Sloan Kettering Cancer Center,
Radiology, New York, New York, USA,
5
Memorial Sloan Kettering Cancer
Center, Epidemiology and Biostatistics, New York, USA,
6
Memorial Sloan
Kettering Cancer Center, Medicine; Currently employed at AstraZeneca,
New York, USA
Introduction: Management of earlystage follicular lymphoma (FL) is
widely variable. We utilized our Follicular Lymphoma Outcomes
Database (FLOD) to assess outcomes and understand the role of
initial observation in patients (pts) with earlystage FL.
Methods: We retrospectively identified 295 pts with grade 13A,
stage III FL diagnosed between 1998 and 2009 at Memorial Sloan
Kettering Cancer Center while excluding pts with fully resected
disease, incomplete imaging at diagnosis, and pts not prescribed rit-
uximab in frontline systemic therapy. Pts were categorized as
immediately treated if localized or systemic treatment was started
within 6 months of diagnosis. Pts were stratified by age at diagnosis
(years): 2040 vs. 4060 vs. 6075 vs. 7595, to analyze the per-
centage of immediate treatment or observation in each group.
Results: In the cohort, 137 (46%) pts were initially observed, and 158
(54%) pts received immediate treatment, consisting of radiation
(n =108), systemic treatment (n =29), or combined modality
treatment (n =21). With a median followup of 8.4 years (range 0.3
17.2), the estimated 10year overall survival (OS) and disease
182
-
SUPPLEMENT ABSTRACTS
specific survival (DSS) were 87.2% (95% confidence interval [CI]:
0.830.92) and 95.6% (95%CI: 0.930.98), respectively. Age at diag-
nosis did not influence selection of pts for observation or immediate
treatment (p value 0.98 and 0.75, respectively for stage I and II pts).
In 172 pts with stage I disease, 112 (65%) were immediately treated,
while 60 (35%) were observed. In 123 pts with stage II FL, 46 (37%)
were immediately treated and 77 (63%) were observed. OS in
observed pts was similar to that of immediately treated stage I or
stage II pts (hazard ratio [HR]: 1.51, p =0.41, Fig. A; HR: 0.74, p =
0.48, Fig. D). In stage I or II pts with complete staging with bone
marrow biopsy and PET, OS between observed and immediately
treated pts remain similar (HR: 4.01, p =0.10, Fig. B, HR: 0.25, p =
0.17, Fig. E). The median time to first therapy for pts initially
observed with stage I and II disease were 4.73 years (95% CI: 2.66
NR, Fig. C) and 6.90 years (95% CI 4.15NR, Fig. F), respectively.
Complete staging did not alter median time to first therapy signifi-
cantly. PFS for immediately treated pts at 5, and 10 years were
67.6%, and 44.6% for stage I disease, and 46.8%, and 32.2% for stage
II disease. Biopsyproven transformation risk using a competing risk
analysis was 4.2% and 10.8% at 5 and 10 years.
Conclusions: This modernera analysis confirms the excellent out-
comes of earlystage FL. Age at diagnosis did not guide selection of
pts for initial observation. Pts selected for observation had a long
duration of observation and similar survival to pts selected for im-
mediate treatment, suggesting initial observation remains an option
in pts with earlystage FL. Transformation risk endures in earlystage
FL supporting continual pts monitoring.
The research was funded by: P30 CA008748
Keywords: Indolent nonHodgkin lymphoma
Conflicts of interests pertinent to the abstract
L. Falchi
Consultant or advisory role: Genmab.
Research funding: Roche, Genmab.
P. A. Hamlin
Consultant or advisory role: Portola Pharmaceutics, Celgene, Kar-
yopharm, Juno Therapeutics.
Research funding: Portola, Molecular Templates, Incyte, J&J
Pharmaceuticals.
S. M. Horwitz
Consultant or advisory role: ADCT therapeutics, Aileron,Corvus,
FortySeven, Innate Pharma, KyowaHakkaKirin, Millenium/Takeda,
Mundipharma, Portola, Seattle Genetics.
Research funding: ADCT therapeutics, Aileron, Celgene, FortySeven,
Infinity/Verastem, KyowaHakkaKirin, Millenium/Takeda, Seattle
Genetics, Trillium.
E. Joffe
Consultant or advisory role: AstraZeneca, Epizyme.
A. Kumar
Consultant or advisory role: Celgene.
Research funding: Abbvie, Adaptive Biotechnologies, Celgene, Phar-
macyclics, Seattle Genetics.
M. J. Matasar
Consultant or advisory role: Genentech, Bayer, Merck, Juno, Roche,
Teva, Rocket Medical, Seattle Genetics.
Honoraria: Genentech, Roche, Bayer, Pharmacyclics, Janssen, Seattle
Genetics, GlaxoSmithKline.
Research funding: Genentech, Roche, GlaxoSmithKline, Bayer, Phar-
macyclics, Janssen, Rocket Medical, Seattle Genetics.
Educational grants: Genentech, Roche, Seattle Genetics, Bayer.
A. J. Moskowitz
Consultant or advisory role: Kyowa Hakko Kirin Pharma, Miragen
Therapeutics, Takeda Pharmaceuticals, ADC therapeutics, Seattle
Genetics, Cell Medica, BristolMyers Squibb, Erytech Pharma.
Research funding: Incyte, Seattle Genetics, BMS, and Merck.
A. Noy
Consultant or advisory role: Janssen, Pharmacyclics, Medscape,
Targeted Oncology.
Research funding: Pharmacyclics, NIH, Raphael Pharma.
L. M. Palomba
Honoraria: Merck, Celgene, Juno and Pharmacyclics.
D. Straus
Consultant or advisory role: Seattle Genetics.
Research funding: Seattle Genetics.
G. von Keudell
Research funding: Pharmacyclics, Merck, Epizyme.
A. D. Zelenetz
Consultant or advisory role: Genentech/Roche, Kite/Gilead, Quant
Health, Astra Zeneca; Karyopharm, Adaptive Biotechnology; Mor-
phoSys, JUNO/Celege/BMS, BeiGene, Verastem.
Research funding: MEI Pharma, Genentech/Roche, BeiGene, Adap-
tive BIotechnology.
A. Dogan
Honoraria: Corvus Pharmaceuticals, Physicians’ Education Resource,
Seattle Genetics, Takeda, Roche, EUSAPharma, PeerView.
Research funding: Roche and Takeda.
G. Salles
Consultant or advisory role: Abbvie, Beigene, BMS/Celgene, Debio-
pharm, Genentech/Roche, Genmab, Incyte, Ipsen, Kite/Gilead, Mil-
teniy, Morphosys, Novartis, Velosbio.
A. Younes
Employment or leadership position: Employed by AstraZeneca.
Consultant or advisory role: Biopath, Xynomics, Epizyme, Roche.
Honoraria: Janssen, AbbVie, Merck, Curis, Epizyme, Roche, Takeda.
Research funding: Janssen, Curis, Merck, BMS, Syndax, and Roche.
C. L. Batlevi
Honoraria: Dava Oncology.
Research funding: Janssen, Novartis, Epizyme, Xynomics.
SUPPLEMENT ABSTRACTS
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183
121 |EARLY METABOLIC RESPONSE IN FOLLICULAR
LYMPHOMA: A SUBSET ANALYSIS OF THE FOLL12 TRIAL BY THE
FONDAZIONE ITALIANA LINFOMI (FIL)
S. Luminari
1
, L. Guerra
2
, R. Durmo
3
, S. Chauvie
4
, S. Peano
5
,
A. Franceschetto
6
, F. Fallanca
7
, V. Tarantino
8
, A. Pinto
9
, C. Ghiggi
10
,
A. Pulsoni
11
, M. Merli
12
, L. Farina
13
, M. Tani
14
, B. Botto
15
,
G. Musuraca
16
, B. Falini
17
, F. Ballerini
18
, P. M. Stefani
19
, S. Bolis
20
,
G. Pietrantuono
21
, M. Manni
22
, L. Marcheselli
23
, M. Federico
22
,
A. Versari
3
1
Azienda Unità Sanitaria Locale IRCCS, Arcispedale Santa Maria Nuova
IRCCS, Hematology Unit and University of Modena and Reggio Emilia,
Surgical, Medical and Dental Department of Morphological Sciences
related to Transplant, Oncology and Regenerative Medicine, Reggio Emilia,
Italy,
2
S. Gerardo Hospital, University of MilanoBicocca, Nuclear Medi-
cine and , University of Milano Bicocca, School of Medicine and Surgery,
Monza, Italy,
3
Azienda USLIRCCS di Reggio Emilia, Nuclear Medicine,
Reggio Emilia, Italy,
4
Santa Croce e Carle Hospital, Department of Medical
Physics, Cuneo, Italy,
5
ASO S. Croce e Carle, S.C. Medicina Nucleare,
Cuneo, Italy,
6
Modena Cancer Center, University of Modena and Reggio
Emilia, Department of Oncology and Hematology, Unit of Nuclear Medi-
cine, Modena, Italy,
7
IRCCS San Raffaele Scientific Institute, Nuclear
Medicine Unit, Milano, Italy,
8
University of Modena and Reggio Emilia,
PhD program in Clinical and Experimental Medicine (CEM), Modena, Italy,
9
National Cancer Institute, Fondazione “G. Pascale” IRCCS, Hematology
Oncology and Stem Cell Transplantation Unit, Napoli, Italy,
10
IRCCS San
Martino Hospital, Hematology and Transplant Center Division, Genoa,
Italy,
11
Sapienza Università di Roma, Dipartimento di Biotecnologie Cel-
lulari ed Ematologia, Roma, Italy,
12
University Hospital Ospedale di Cir-
colo e Fondazione Macchi, ASST Settelaghi, Varese, Italy,
13
Fondazione
IRCCS Istituto Nazionale dei Tumori di Milano , Division of Hematology,
Milano, Italy,
14
Ospedale Civile S Maria delle Croci, Azienda Unità Sani-
taria Locale (AUSL), Ravenna, Italy,
15
A.O.U. Città della Salute e della
Scienza di Torino, SC Ematologia, Torino, Italy,
16
IRCCS Istituto Romag-
nolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Department of He-
matology, Meldola, Italy,
17
University of Perugia, Institute of Hematology
and CREO (Center for HematoOncological Research), Ospedale S. Maria
della Misericordia, Perugia, Italy,
18
IRCCS Ospedale Policlinico San Mar-
tino, University of Genoa, Clinica Ematologica, Genova, Italy,
19
General
Hospital Ca' Foncello, Hematology, Treviso, Italy,
20
ASST MONZA, SC di
Ematologia, Monza, Italy,
21
IRCCS Centro di Riferimento Oncologico della
Basilicata, Hematology and Stem Cell Transplantation Unit, Rionero in
Vulture, Italy,
22
University of Modena and Reggio Emilia, Surgical, Medical
and Dental Department of Morphological Sciences related to Transplant,
Oncology and Regenerative Medicine, Modena, Italy,
23
Fondazione Ital-
iana Linfomi Onlus, FIL, Modena, Italy
Background: A small but significant proportion of patients with
Follicular Lymphoma (FL) shows an aggressive behavior. Among
available prognostic tools the duration of response and metabolic
response (MR) after completion of immunochemotherapy (ICT)
(fPET) were confirmed with a strong correlation with both PFS and
OS. So far, only few data are available to define the role of an earlier
assessment of MR during the ICT in FL. In the FOLL12 randomized
trial we evaluated the efficacy of a response adapted post induction
management of patients with FL responding to initial ICT. In a sig-
nificant proportion of patients, MR was also assessed during the
administration of ICT as one of the admitted study procedures. We
here show the details of early assessment of MR and its correlation
with patient outcomes.
Methods: The FOLL12 trial enrolled treatment naïve adult patients
with grade 13a, stage IIIV and a high tumor burden FL. Complete
FIGURE 1 A)Progression free Survival(PFS) by interim metabolic evaluated with FDSPETR at cycle 4 of induction therapy(iPET):B)PFS by
iPET and metabolic response at end of indication PET(fPET)
184
-
SUPPLEMENT ABSTRACTS
metabolic response (CMR) was centrally assessed at End of Induction
(EOI; fPET) using the 5point Deauville scale (DS). In this study we
included only patients for whom MR was also assessed during ICT
between cycle 4 and 5 (iPET). iPET results were defined on the basis of
the local report and were also centrally reviewed applying standard DS.
The primary endpoint was 3year Progression Free Survival (PFS).
Results: iPET was performed in 211/807 patients enrolled in the
FOLL12 trial and local report was available in 186 cases. Fortyeight
percent of patients were older than 60 years, 37% had a highrisk
FLIPI2, 44% received BR as induction ICT. Based on local report
iPET was considered positive in 38/186 patients (20%). iPET and
fPET were both available for comparison in 174 cases and showed a
concordance rate of 82%: 131 out of 140 iPETconfirmed their CMR
at fPET (94%). Regarding the 31 iPET+, a fPETwas achieved in 23
cases (68%). In univariable analysis, the 3year PFS was lower for the
iPET+patients compared to the iPET(52% vs 87%: HR of 2.73 95%
CI 1.51 4.95) (Fig 1A). Considering both iPET and fPET, a positive
iPET was associated with an increased risk of progression also if a
negative fPET was achieved (HR 2.09: 95% CI3.22 19.5) (Fig 1B).
iPET was also associated with a different 3year OS rate (99% vs 89%
for iPET vs +; p =0.035). In multivariable analysis the prognostic
role of iPET for PFS was confirmed (HR 2.60 (1.41 4.79) and was
independent from FLIPI2 (02 vs 35 HR 1.88 (1.05 3.35)), and for
ICT (RB vs RCHOP (HR 1.39 (0.77 2.51)). The centralized review of
iPET response according to DS is ongoing.
Conclusions: Interim metabolic response is confirmed with a strong
prognostic role for PFS in patients with advanced stage FL treated
with standard ICT. Considering the higher rates of iPET+cases
compared to fPET, iPET may better contribute to anticipate the
identification of FL patients at different risk of progression and might
be used to define a novel generation of response adapted trials in FL.
The research was funded by: Società Italiana di Ematologia (SIE)
Associazione Angela Serra per la Ricerca sul Cancro
Ministero della Salute, Direzione Generale della ricerca e dell’In-
novazione in sanità (BANDO PROGETTI DI RICERCA GIOVANI
RICERCATORI RICERCA FINALIZZATA 20112012)
Keywords: Diagnostic and Prognostic Biomarkers, PETCT, Indolent
nonHodgkin lymphoma
No conflicts of interest pertinent to the abstract.
122 |THE ROLE OF FDGPET/CT AND BONE MARROW BIOPSY
IN DETECTING BONE MARROW INVOLVEMENT IN THE INITIAL
STAGING OF FOLLICULAR LYMPHOMA: AN ANALYSIS OF
ACCURACY AND PROGNOSTIC IMPACT
L. Reguilón Gallego
1
, T. Chen Liang
2
, T. Martín Santos
3
, A. Salar
4
, M.
Fernández González
5
, C. Celades
6
, J. Tomás Navarro
7
, A.B.
Martínez
8
, R. Andreu
9
, A. Balaguer Rosello
9
, A. Martín
10
, M. Baile
10
,
J. López Jiménez
11
, J. Marquet
11
, A.I. Teruel
12
, M.J. Terol
12
, C.
Benet
13
, L. Frutos
14
, J.L. Navarro
14
, J. Uña
15
, M. Suarez
16
, M.
Cortes
17
, J. Contreras
18
, C. Ruiz
19
, P. Tamayo
20
, J. Mucientes
21
, P.
Sopena Novales
22
, J.J. Sánchez Blanco
1
, E. Pérez Ceballos
1
, A. Jeréz
Cayuela
1
, F. Ortuño
1
1
Hospital Morales Meseguer, IMIBArrixaca, Servicio de Hematología y
Oncología Médica, Murcia, Spain,
2
Hospital Morales Meseguer, IMIB
Arrixaca, Servicio de Hematología y Oncología Médica, Murcia, Spain,
3
Hospital Universitario de Canarias, Servicio de Hematología, La Laguna,
Tenerife, Spain,
4
Hospital del Mar, Servicio de Hematología, Barcelona,
Spain,
5
Hospital Universitario de Canarias, Servicio de Hematología, La
Laguna, Tenerife, Spain,
6
Josep Carreras Leukaemia Research Institute
(IJC), Servicio de Hematología, Badalona, Spain,
7
ICOH. Germans Trias i
Pujol, Servicio de Hematología, Badalona, Spain,
8
Hospital Santa Lucía,
Servicio de Hematología, Cartagena, Spain,
9
Hospital La Fe, Servicio de
Hematología, Valencia, Spain,
10
Hospital Clínico Universitario de Sala-
manca, Servicio de Hematología, Salamanca, Spain,
11
Hospital Ramón y
Cajal, Servicio de Hematología, Madrid, Spain,
12
Hospital Clinico de
Valencia, Servicio de Hematología, Valencia, Spain,
13
Hospital Arnau de
Villanova, Servicio de Hematología, Valencia, Spain,
14
Hospital Virgen de la
Arrixaca, Servicio de Medicina Nuclear, Murcia, Spain,
15
Hospital Uni-
versitario Nuestra Señora de la Candelaria, Servicio de Medicina Nuclear,
Tenerife, Spain,
16
Hospital del Mar, Servicio de Medicina Nuclear, Barce-
lona, Spain,
17
Hospital Universitari de BellvitgeIDIBELL, Servicio de
Medicina Nuclear, Barcelona, Spain,
18
Hospital Santa Lucia, Servicio de
Medicina Nuclear, Cartagena, Spain,
19
Hospital La Fe, Servicio de Medicina
Nuclear, Valencia, Spain,
20
Hospital Clínico Universitario de Salamanca/
IBSAL, Servicio de Medicina Nuclear, Salamanca, Spain,
21
Hospital Puerta
de Hierro, Servicio de Medicina Nuclear, Madrid, Spain,
22
Hospital 9 de
Octubre, Servicio de Medicina Nuclear, Valencia, Spain
Introduction: In the workout of Follicular nonHodgkin Lymphoma
(FL), bone marrow assessment by bone marrow biopsy (BMB) is a key
component of Follicular Lymphoma International Prognostic Index2
(FLIPI2) and progression of disease within 24 months of frontline FL
chemoimmunotherapy initiation (POD24) models. Nevertheless, in
several recent studies, positron emission tomography combined with
computed tomography (PET/CT) identification of BMI was shown to be
predictive of progressionfree survival (PFS) and overall survival (OS)
Methods: To evaluate the independent value of BMB and/or PET/CT
to determine bone marrow infiltration (BMI) and their prognostic
impact, we have carried out a retrospective multicenter study
including FL patients with both tests at diagnosis. The diagnosis ac-
curacy and the prognosis impact for PFS and OS, and within FLIPI2
and POD24 models of each technique were analyzed. To avoid
collinearity biases FLIPI2 was deconstructed and its five parameters
were considered independently. In addition, further adjustments
were performed stratifying the whole series by treatment intensity
and histologic grade.
Results: Three hundred two patients were included. Their median age
was 58.3 years, and 50.3% (152 of 302) were female. One hundred
sixtyone patients (53.3%) had stage IV disease (based on combined
BMB and PET/CT results). The prognostic index scales, FLIPI and
FLIPI2, were low risk in 27.5% and 29.5%, respectively. Most pa-
tients had histological grade 12 disease (66.9%). The most common
firstline chemotherapy regimen for advancedstage patients was
SUPPLEMENT ABSTRACTS
-
185
rituximab with cyclophosphamide, doxorubicin, vincristine, and
prednisone in 159 patients (52.6%).
BMI was detected in 170 and 69 patients by BMB and PET/CT
respectively. Sensitivity and accuracy were 46% and 73.2% for PET/CT
and 84.3% and 92.4% for BMB respectively. In univariate analysis both
PET/CT (p=0.043; p=0.01) and BMB (p=0.004; p=0.029) correlated
with PFS and OS, respectively. In a multivariate analysis involving the
whole series, only BMIBMB (P=0.043), but not BMIPETCT corre-
lated with PFS. When considering those patients who received
intensive treatment, only BMIBMB (p=0.004; p=0.032) correlated
with PFS and OS, respectively. Among histologic grade 3a patients,
only BMIBMB (p=0.01; p=0.009) correlated with PFS and OS,
respectively. However, in other histologic grades (<3), BMIBMB (P=
0.009) only correlated with PFS. BMIBMB (P=0.03) added inde-
pendent prognostic value to POD24 in the multivariate analysis.
When PET/CT was used as positive BMI instead of BMB, it only
added independent prognostic value in the intensive treatment
cohort model (p=0.026) and just for OS.
Conclusions: In our FL series, BMI assessment by BMB was superior
to that of PET/CT in both performance and prognosis and reinforce
the need to carry out BMB for adequately fulfill FLIPI2.
Keywords: PETCT, Indolent nonHodgkin lymphoma
No conflicts of interest pertinent to the abstract.
123 |CLINICAL UTILITY OF INTERIM CT SCANS IN PATIENTS
RECEIVING CHEMOIMMUNOTHERAPY FOR FIRST LINE
TREATMENT OF FOLLICULAR LYMPHOMA
F. Manji
1
, S. Bhella
1
, R. Kridel
1
, V. Kukreti
1
, J. Kuruvilla
1
, A. Prica
1
, M.
Crump
1
1
Princess Margaret Cancer Centre, Department of Medical Oncology and
Hematology, Toronto, Canada
Interim imaging with computed tomography scanning (CT) has been
performed midway through treatment during most clinical trials of
chemoimmunotherapy in patients with follicular lymphoma (FL)
receiving first line systemic therapy. Based on this, interim imaging is
commonly performed, but there is little evidence of its utility in clinical
practice.
The objective of this study was to retrospectively review the
outcomes of interim CTs (iCT) in adult patients with biopsy proven FL
(grade 13a, 3b excluded) who met criteria for treatment and
received first line therapy with rituximab with cyclophosphamide,
vincristine and prednisone (RCVP) or bendamustine and rituximab
(BR) at Princess Margaret Cancer Centre from January 1 2003
December 31 2018. Baseline patient characteristics and treatment
were retrieved from a prospectively populated database, and results
of interim and end of treatment CTs were evaluated from the elec-
tronic medical record. Disease response was assessed using Lugano
response criteria as partial response (PR), complete response (CR),
stable disease (SD) or progressive disease (PD). Descriptive statistics
and Kaplan Meier Survival functions with a log rank test were used
for analysis. The study was approved by the Princess Margaret
Research Ethics Board.
A total of 190 patients were identified: mean age at diagnosis 58.6
years (IQR 49.267.8), 78% with stage III/IV disease, 26.8% bulky
(>10cm) and 41.1% FLIPI score >2. Patients received either 68 cycles
of RCVP (n =69, 36.3%) or 6 cycles of BR (n =121, 63.7%) with a
median follow up of 75 months (range 6.6204.0 months). Most pa-
tients (n =177,93.1%) had interim imaging done between the end of
cycle 2 and prior to cycle 5, most commonly CT scan (n =174,91.5%).
Most iCTs showed a PR (n =147, 77.4 %), with a minority showing a CR
(n =15, 7.9%) and SD (n =8, 4.2 %). Seven patients (3.7%) had PD noted
on iCT. Four patients had a second malignancy identified on repeat
biopsy of lesions found on iCT (thymoma, poorly differentiated carci-
noma, lung adenocarcinoma and spindle cell tumour), 2 of whom were
symptomatic at the time of imaging. Of the 3 remaining patients, 2 were
symptomatic at the time of iCT and only 1 had asymptomatic PD; all 3
had biopsies demonstrating transformation to diffuse large B cell
lymphoma (DLBCL). The 3 year PFSof all patients was85.29%. Patients
with a PR on iCT had similar 3 year PFS compared to those with CR
(86.25% vs 85.71%, p =.80) as well as overall survival (94.46% vs
92.31%, p =0.58).
Conclusion: iCT is not useful in identifying patients with asymptomatic
early progression of FL during frontline treatment with BR or RCVP.
The majority of patients receiving systemic treatment for FL with BR
or RCVP have at least a PR on iCT, which is not associated with inferior
PFS or OS compared to those with CR. Patients with symptomatic or
asymptomatic PD during treatment warrant biopsy to identify histo-
logic transformation or other malignancies.
EA previously submitted to ASCO 2021.
The research was funded by: The Princess Margaret Cancer
Foundation
Keywords: Indolent nonHodgkin lymphoma
Conflicts of interests pertinent to the abstract
S. Bhella
Consultant or advisory role: Celgene
R. Kridel
Research funding: Gilead Sciences, Roche
V. Kukreti
Consultant or advisory role: Kirin Kyoto
J. Kuruvilla
Consultant or advisory role: Abbvie, BMS, Gilead, Karyopharm,
Merck, Roche, Seattle Genetics
Honoraria: Amgen, Antengene, Astra Zeneca, BMS, Gilead, Incyte,
Janssen, Karyopharm, Merck, Novartis, Pfizer, Roche, Seattle Ge-
netics, TG Therapeutics
Research funding: Canadian Cancer Society, Leukemia and Lym-
phoma Society Canada, Princess Margaret Cancer Foundation,
Janssen, Roche, Astra Zeneca
186
-
SUPPLEMENT ABSTRACTS
Other remuneration: Lymphoma Canada (Chair)
A. Prica
Honoraria: AstraZeneca, Gilead
M. Crump
Honoraria: Kite/Gilead, Novartis, Servier
Research funding: Roche, epizyme
124 |WITHDRAWN
125 |EVALUATION OF FOUR PROGNOSTIC INDEXES IN FIRST
LINE FOLLICULAR LYMPHOMA TREATED WITH
IMMUNOCHEMOTHERAPY
C. FernándezRodríguez
1
, R. DiezFeijoo Varela
2
, B. Sanchez
Gonzalez
2
, L. Bento
3
, L. FernándezIbarrondo
1
, J. Gibert
1
, M.
Lafuente
1
, J. J. RodriguezSevilla
2
, S. Pinzón
2
, B. Espinet
1
, A. Ferrer
1
,
E. Gimeno
2
, J. F. García
4
, R. Ramos
5
, B. Bellosillo
1
, A. Gutierrez
3
, L.
Colomo
1
, A. Salar
2
1
Hospital del Mar, Pathology, Barcelona, Spain,
2
Hospital del Mar,
Hematology, Barcelona, Spain,
3
Hospital Son Espases, Hematology, Palma
de Mallorca, Spain,
4
MD Anderson Cancer Center, Pathology, Madrid,
Spain,
5
Hospital Son Espases, Pathology, Palma de Mallorca, Spain
Introduction: Several models have been proposed to predict treat-
ment outcome in follicular lymphoma (FL). A new prognostic model
(m7FLIPI) incorporated clinical data and mutational status of seven
genes (EZH2, ARID1A, MEF2B, EP300, FOXO1, CREBBP and
CARD11) to predict treatment outcome with frontline immnuo-
chemotherapy (RCHOP and RCVP). This model needs further pro-
spective validation in other widely used regimens, such as R
bendamustine (RB) and also in the realworld setting.
Methods: Retrospective study from 3 centers that included consec-
utive patients with FL grade 13a treated in first line with RCVP, R
CHOP or RB. FFPE tissue from diagnostic lymph node biopsies were
studied by NGS (QIAgen custom DNA panel covering the entire
coding region of 64 genes, including those in the M7FLIPI). Gene
libraries were sequenced using Illumina technology.
Results: A total of 191 patients with newly diagnosed FL have been
included in this cohort analysis, with a final number of 109 cases with
complete clinical data and successful characterization by NGS. Me-
dian age at diagnosis was 58 years (range 2490), 56% were males
and 93.6% had stage IIIIV. Immunochemo was: RCVP in 7.3%, R
CHOP in 65.1% and RB in 27.5%. Overall response rate was
98.2% (CR 83.5%). Maintenance rituximab was administered in
79.8%. With a median followup of 96 months, PFS and OS at 8 years
were 55% and 80%, respectively.
All patients presented mutations (median 8 per patient; range
223). Frequency of m7FLIPI genes: EZH2 (23%), ARID1A (17%),
MEF2B (19%), EP300 (19%), FOXO1 (10%), CREBBP (75%),
CARD11 (17%).
FLIPI score was (n =105): low in 18 (17%), intermediate in 45
(43%), high in 42 (40%). m7FLIPI score was: low in 81 (77%) and high in
24 (23%). No case with lowintermediate FLIPI score was upgraded in
m7FLIPI. However, 18 out of 42 highrisk cases in FLIPI were down-
graded to lowrisk m7FLIPI. Discrimination according to 4 prognostic
indexes is shown (table). Intriguingly, when RB patients were sepa-
rately analyzed, m7FLIPI outperformed the other 3 scores for PFS and
OS (log rank/p: 2.818/0.093 and 5.667/0.017, respectively).
Conclusions: In the realworld setting, all prognostic systems inves-
tigated (FLIPI, FLIPI2, PRIMA and m7FLIPI) are useful to identify
patients with different survival probabilities after treatment with
immunochemotherapy, including RB. However, FLIPI remains the
prognostic index with higher discrimination.
Acknowledgements: Supported in part by ISCIII, PI15/0459, GLD18/
00117, PI19/0034, 2017SGR205, PT17/0015/0011 and Xarxa de
Banc de Tumors de Catalunya.
The research was funded by: This study was supported in part by
ISCIII, PI15/0459, GLD18/00117, PI19/0034, 2017SGR205, PT17/
0015/0011 and Xarxa de Banc de Tumors de Catalunya.
Keywords: Diagnostic and Prognostic Biomarkers
Conflicts of interests pertinent to the abstract
A. Salar
Consultant or advisory role: Celgene, Janssen
Research funding: Gilead
126 |ANALYSIS OF EZH2 MUTATIONS IN SOLID AND LIQUID
BIOPSY AND ITS ROLE AS PREDICTIVE BIOMARKER FOR
CHEMOTHERAPY IN PATIENTS WITH FOLLICULAR LYMPHOMA
L. SanzVillanueva
1
, F. Díaz Crespo
2
, R. Martín Rojas
3
, D. Carbonell
1
,
M. Chicano
1
, J. SuárezGonzález
4
, P. Muñiz
1
, J. Menárguez
5
, M. Kwon
1
,
J. L. Diez Martín
6
, I. Buño
7
, C. MartínezLaperche
1
, M. Bastos Oreiro
1
1
Gregorio Marañón Health Research Institute (IiSGM). Gregorio
Marañón General University Hospital, Department of Hematology,
Madrid, Spain,
2
Gregorio Marañón Gregorio Marañón General
University Hospital, Pathology Department, Madrid, Spain,
3
Gregorio
Marañón General University Hospital, Department of Hematology,
PFS OS
Log rank
test; p
C
index
Log rank
test; p
C
index
FLIPI (lowintermediate
vs high)
11.432;
0.001
0.6435 11.881;
0.001
0.7268
FLIPI2 (low vs
intermediatehigh)
7.038;
0.008
0.5608 6.031;
0.014
0.6023
PRIMA (low vs
intermediatehigh)
7.585;
0.006
0.592 2.057;
0.152
0.6204
m7FLIPI (low vs high) 3.146;
0.076
0.6037 3.546;
0.060
0.5737
SUPPLEMENT ABSTRACTS
-
187
Madrid, Spain,
4
Gregorio Marañón Health Research Institute (IiSGM).
Gregorio Marañón General University Hospital, Genomics Unit, Madrid,
Spain,
5
Gregorio Marañón General University Hospital, Department of
Hematology and Pathology, Madrid, Spain,
6
Gregorio Marañón Health
Research Institute (IiSGM). Gregorio Marañón General University
Hospital, Department of Hematology. Complutense University of
Madrid, Department of Medicine, Madrid, Spain,
7
Gregorio Marañón
Health Research Institute (IiSGM). Gregorio Marañón General University
Hospital, Department of Hematology and Genomics Unit. Complutense
University of Madrid, Department of Cellular Biology, Madrid, Spain
Introduction: Missense mutations in EZH2 lead to decreased tran-
scriptional function of genes involved in cell cycle regulation and
plasma cell differentiation, contributing to oncogenic transformation.
EZH2 is mutated in near 20% of follicular lymphomas (FL). We aimed
to analyse retrospectively the frequency of mutations in EZH2 at
diagnosis and relapse in tissue and circulating cell free DNA (cfDNA)
in patients with FL and assess the patient's response to therapy,
depending on the EZH2 mutation status.
Methods: We included 179 consecutive patients diagnosed with FL
from 2002 to 2019. Thirtyseven patients were excluded due to
insufficient DNA quantity or quality. Of the 142 analysed patients, 49
had cfDNA sample at diagnosis. DNA was extracted from tissue bi-
opsies using Maxwell(R) 16 FFPE Plus LEV DNA (Promega). We ob-
tained cfDNA from plasma samples, using QIAamp® Circulating
Nucleic Acid (Qiagen). RTqPCR reactions were performed in ctDNA
using PrimeTime Mini LNA probe for EZH2 Y646. Sanger sequencing
were used in tissue DNA for detection of mutations in exon 16
(Y646) and 18 (A682 and A692). Clinical characteristics, therapy and
outcome were collected. Data analysis including descriptive statistics
and Fisher's exact test was performed using IBM SPSS Statistics 26
(IBM, USA).
Results: Of the 142 patients analysed in tissue, 41 (29%) presented
mutations in EZH2 at diagnosis. These mutations were found in 46%
of grade 3B FL and 27% of lowgrade FL (Table 1). Y646N/S/C
mutations in cfDNA were detected in 7/49 (14%) with EZH2
mutated in tissue, 6 of them with stage IIIIV FL. Clinical and bio-
logical characteristics according to EZH2 mutation status in tissue
were compared in patients with lowergrade FL (Table 1) and high
grade 3B. No statistical differences were found in lowergrade FL.
Instead, patients with grade 3B and mutated EZH2 had statistically
higher FLIPI risk (80% vs 0%; p =0.048) (data not shown). EZH2
mutations in tissue were evaluated at relapse in 13 patients and
were found in 2 samples (3 mutated at diagnosis). Overall survival
(OS) of total cohort and according to therapy received and EZH2
mutation status were compared and there were no statistically
significant differences. In terms of progression free survival (PFS),
our results shown that mutated EZH2 patients treated with R
bendamustine were significantly associated with inferior PFS (p =
0.013) (Figure 1A), unlike RCHOP treated patients (p =0.15)
(Figure 1B).
Conclusions: The frequency of EZH2 mutations in our total cohort is
similar to previously reported. Mutations were more frequent in high
grade FL patients. Lowgrade FL patients mutated at diagnosis,
receiving Rbendamustine were associated with inferior PFS. The
mutational status of these patients at diagnosis could be useful to
guide treatment. Detection of EZH2 mutations in cfDNA is possible in
FL, especially for advanced stages.
TABLE 1Clinical characteristic and firstline theraphy in patents with grade 1,2,3A FL.
188
-
SUPPLEMENT ABSTRACTS
Keywords: Diagnostic and Prognostic Biomarkers, Liquid biopsy,
Indolent nonHodgkin lymphoma
No conflicts of interest pertinent to the abstract.
CHRONIC LYMPHOCYTIC LEUKEMIA
127 |CLADRIBINE AS FRONTLINE TREATMENT OF HAIRY CELL
LEUKEMIA: A MULTICENTER EUROPEAN EXPERIENCE OF MORE
THAN 30 YEARS ON 384 PATIENTS
A. Broccoli
1
, L. Argnani
2
, M. Cross
3
, A. Janus
4
, E. Maitre
5
, X.
Troussard
5
, T. Robak
4
, C. Dearden
3
, M. Else
6
, D. Catovsky
6
, P. L.
Zinzani
2
1
IRCCS Azienda OspedalieroUniversitaria di Bologna Istituto di Ema-
tologia “Seràgnoli”, and Dipartimento di Medicina Specialistica, Diag-
nostica e Sperimentale, Università di Bologna, Bologna, Italy,
2
IRCCS
Azienda OspedalieroUniversitaria di Bologna Istituto di Ematologia
“Seràgnoli” and Diagnostica e Sperimentale Università di Bologna,
Dipartimento di Medicina Specialistica, Bologna, Italy,
3
The Royal
Marsden Hospital and The Institute of Cancer Research, Department of
HaematoOncology, London, UK,
4
Copernicus Memorial Hospital ,
Department of Hematology , Lodz, Poland
5
CHU CAEN, Registre des
Hémopathies Malignes de Normandie Occidentale, CAEN CEDEX,
France,
6
The Institute of Cancer Research, Division of Molecular Pa-
thology, London, UK
Introduction. Cladribine is regarded as the first treatment of choice
of symptomatic hairy cell leukemia (HCL) patients, as it is able to
provide high rates of response and very long duration of remission in
some cases.
Methods. Diseasespecific patients records have been reviewed at
four European centers of excellence in the treatment of HCL (Bologna,
Italy; Caen, France; London, United Kingdom, and Lodz, Poland) and all
patients requiring treatment who received frontline cladribine have
been extrapolated for analysis. Responses have been classified ac-
cording to the Consensus Resolution Criteria published in 1987. The
main study objectives were represented by longterm overall survival
(OS), diseasefree survival (DFS) and progressionfree survival (PFS)
rates. PFS calculation involved all patients obtaining at least a partial
response; DFS was determined only in patients with a complete
response (CR) after treatment. Determining events for DFS and PFS
were disease progression (decline in hematologic parameters, reap-
pearance of marrow infiltration and/or organomegaly), initiation of a
subsequent treatment, death for any cause.
Results. Three hundred and eightyfour HCL patients (including 3
patients with HCL variant) have been diagnosed and followed be-
tween 1969 and 2018, and all of them received frontline cladribine
(either subcutaneously or intravenously, according to eraand site
specific guidelines and experience). A CR was obtained in 150
cases (39.1%), a partial response in 50 (13.0%) and a minor response
in 7 (1.8%). Two hundred and eight patients (54.2%) received no
further therapy besides cladribine as they did not require further
treatment for their disease. A continuous CR was documented in 76
patients (19.8%), at a median followup period of 8.5 years (range, 1
22 years). Median OS was reached at 25.0 years, with 48.3% of pa-
tients being alive at 28 years. Median PFS was 13.0 years, with 43%
of patients being free of progression at 22 years. DFS was 26.5% at
22 years, with median reached at 11 years (Figure). Retreatment with
cladribine in relapsed patients occurred in 106 cases.
Conclusions. Cladribine is effective as frontline treatment of HCL and
may determine deep disease control in a significant proportion of
cases, given that more than 50% of treated patients require no further
therapy. Good quality responses may be maintained for more than 20
years in nearly 40% of patients. Data obtained from this large inter-
national cohort of patients recapitulate the results obtained from
smaller singlecenter clinical experiences with purine analogs.
Keywords: Lymphoid Cancers Other
No conflicts of interest pertinent to the abstract.
FIGURE 1 KaplanMeier curves in patients with grade 1, 2, and 3a. A. PFS on days of patents treated with Rbendamustine theraphy; B.
PFS on days of patients treated with RCHOP theraphy. PFS Progressionfree survival
SUPPLEMENT ABSTRACTS
-
189
128 |MOLTO, A MULTICENTER, OPEN LABEL,
UNCONTROLLED, PHASE II CLINICAL TRIAL ON VENETOCLAX,
ATEZOLIZUMAB, OBINUTUZUMAB IN RICHTER
TRANSFORMATION: SAFETY INTERIM ANALYSIS
A. M. Frustaci
1
, A. Tedeschi
1
, P. L. Zinzani
2
, D. Pietrasanta
3
, M.
Coscia
4
, T. Zenz
5
, M. Motta
6
, G. Gaidano
7
, L. Scarfò
8
, M. Deodato
1
, G.
Zamprogna
1
, C. Vitale
4
, R. Cairoli
1
, D. Rossi
9
, M. Montillo
1
1
ASST Grande Ospedale Metropolitano Niguarda, Hematology, Milan,
Italy,
2
“L. e A. Seràgnoli,” University of Bologna, Hematology, Bologna,
Italy,
3
Azienda Ospedaliera SS Arrigo e Biagio e Cesare Arrigo,
Hematology, Alessandria, Italy,
4
A.O.U. Città della Salute e della Scienza di
Torino and Department of Molecular Biotechnology and Health Sciences,
University of Torino, Hematology, Torino, Italy,
5
University Hospital
Zürich and University of Zürich, Hematology, Zurich, Switzerland,
6
ASST
Spedali Civili, Hematology, Brescia, Italy,
7
University of Eastern Piedmont,
Translational Medicine, Division of Hematology, Novara, Italy,
8
Università
VitaSalute San Raffaele and IRCC Ospedale San Raffaele, Hematology,
Milano, Italy,
9
Oncology Institute of Southern Switzerland; Institute of
Oncology Research, Hematology, Bellinzona, Switzerland
Introduction: Diffuse large Bcell (DLBCL) transformation from
chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma
(SLL), Richter Syndrome (RS), has poor prognosis. Single agent ven-
etoclax, as well as atezolizumab+/obinutuzumab showed activity in
heavily pretreated DLBCL. MOLTO is a multicenter international
phase II study (EUDRACT 201800502840) evaluating venetoclax/
atezolizumab/obinutuzumab combination in 28 RS.
Methods: Treatment scheme: 35 cycles with obinutuzumab (1000 mg
C18), atezolizumab (1200 mg C118) and venetoclax (400 mg/diC1
35), in untreated DLBCLRS. At initial safety run phase 9 patients
(pts) received at least 3 courses with the possibility of premature
enrollment stop in case of 3 noninfective/nonhematologic
therapyrelated G 4 adverse events (AEs). Remaining pts received
same schedule of safety cohort.
Results: From October 2019, in the absence of safety warning
enrollment went on and, as of February 2021, 14 pts received at least
1 cycle. In table 1 are shown pts characteristics. Overall, 110 cycles
have been administered. Five serious AE (SAEs) were recorded in 4
pts: 1 fever of unknown origin (FUO) and 1 autoimmune encephalitis,
both G3, resolved and not leading to discontinuation, and 1 G5
pneumonia. The remaining 2 SAEs were related to hospitalization due
to disease progression (PD). Twelve/14 pts (85.7%) developed G1
AE of any grade. Severe (G 35) hematological toxicity occurred in 7
pts, while 5 pts (including 2 developing SAEs) experienced severe
nonhematological toxicity. The most common hematological toxicity
was thrombocytopenia: 20 episodes/110 courses (18.2%), 9 being
G3. Other G 3 hematologic toxicities: 10% neutropenia and 0.9%
anemia. Three severe nonhematological toxicities were recorded: 1
hyperamylasemia; 1 hypercalcemia; 1 purpura. Seven pts (50%)
showed grade 2 FUO and only 1 major infection was observed. Two
were the AE of special interest: 1 autoimmune myositis and 1 auto-
immune encephalitis both successfully managed with steroids. No
G3 infusion related reactions (IRR) occurred and all G1/2 were
obinutuzumabrelated. All pts completed venetoclax rampup, in 2
cases with accelerated doseescalation (Koening et al. 2020) due to
rapidly PD. No tumor lysis syndrome (TLS) was recorded. Overall, 9
pts are still on treatment with a median time on study of 4.4 (range 1
16.7) months, only 1/5 pts discontinued due to toxicity.
Conclusions: Treatment with venetoclax, obinutuzumab and atezo-
lizumab was well tolerated even in elderly, and the Independent Data
Monitoring Committee allowed the accomplishment of safety run
phase. Obinutuzumabatezolizumab combination did not result in an
enhanced IRR rate or severity. In this highly proliferating disease,
venetoclax did not lead to TLS even with the accelerated rampup.
TABLE 1Patitent' characteristics
190
-
SUPPLEMENT ABSTRACTS
Accrual is ongoing, and updated results will be presented at the
meeting.
EA previously submitted to EHA 2021.
The research was funded by: HoffmannLa Roche
Keywords: Aggressive Bcell nonHodgkin lymphoma, Chronic Lym-
phocytic Leukemia (CLL), Combination Therapies
No conflicts of interest pertinent to the abstract.
129 |PIRTOBRUTINIB (LOXO305), A NEXT GENERATION
HIGHLY SELECTIVE NONCOVALENT BTK INHIBITOR IN
PREVIOUSLY TREATED RICHTER TRANSFORMATION: RESULTS
FROM THE PHASE 1/2 BRUIN STUDY
W. Jurczak
1
, N. N. Shah
2
, N. Lamanna
3
, T. A. Eyre
4
, J. Woyach
5
, E.
LechMaranda
6
, W. G. Wierda
7
, D. Lewis
8
, M. C. Thompson
9
, D.
Wang
10
, M. Yin
10
, M. Balbas
11
, B. C. Nair
11
, E. Y. Zhu
11
, D. E. Tsai
12
,
N. C. Ku
12
, C. C. Coombs
13
, A. R. Mato
9
1
Maria SklodowskaCurie National Research Institute of Oncology, Clin-
ical Oncology, Krakow, Poland,
2
Medical College of Wisconsin, Hematol-
ogy and Oncology, Brookfield, USA,
3
Herbert Irving Comprehensive
Cancer Center, Columbia University, Medicine, New York, USA,
4
Oxford
University Hospitals NHS Foundation Trust, Churchill Cancer Center,
Haematology, Oxford, UK,
5
The Ohio State University Comprehensive
Cancer Center, Internal Medicine, Columbus, USA,
6
Institute of Hema-
tology and Transfusion Medicine, Hematology, Warsaw, Poland,
7
MD
Anderson Cancer Center, Leukemia, Houston, USA,
8
Plymouth Hospitals
NHS Trust Derriford Hospital, Haematology, Plymouth, UK,
9
Memorial
Sloan Kettering Cancer Center, Medicine, New York, USA,
10
Loxo
Oncology at Lilly, Statistics, Stamford, USA,
11
Loxo Oncology at Lilly,
Clinical, Stamford, CT, USA,
12
Loxo Oncology at Lilly, Medical, Stamford,
CT, USA,
13
University of North Carolina at Chapel Hill, Medicine, Chapel
Hill, USA
Introduction: Richter transformation (RT) is the development of an
aggressive large cell lymphoma in the setting of underlying CLL and is
a recurrent reason for treatment failure (515%) among patients (pts)
receiving CLL directed therapy. Outcomes for pts with relapsed RT
are extremely poor, with no standard treatment and overall survival
estimated at 58 months. Pirtobrutinib is a highly selective and
potent noncovalent BTK inhibitor (BTKi) with high oral bioavail-
ability and a long halflife, resulting in robust BTK target coverage
even in highgrade malignancies with high BTK protein turnover.
Here we report the safety and efficacy of pirtobrutinib in previously
treated pts with RT.
Methods: Pts with previously treated RT were enrolled to either the
dose escalation or expansion portion of the phase 1/2 BRUIN study
(NCT03740529). The primary endpoint for this analysis was ORR per
Lugano criteria. A key secondary endpoint was duration of response.
Efficacy evaluable pts included all dosed RT pts who underwent their
first response evaluation or discontinued therapy as of the data cut.
Results: As of 27 September 2020, 323 pts with Bcell malignancies
were treated including 9 pts with previously treated RT (8 of 9 RT pts
received the RP2D of 200mg QD, 1 pt received 150mg QD). All 9 pts
had received 1 prior RT directed therapy, and the median number
of prior RT directed therapies was 2 (range 15). Pts had received a
median of 4 prior lines of therapy for CLL (range 06). Prior RT
directed therapies included chemoimmunotherapy (100%, n =9),
covalent BTKi (44%, n =4), antiPD1 or PDL1 antibody (33%, n =
3), mTOR inhibitor (22%, n =2), PI3K inhibitor (22%, n =2), CART
cell therapy (n =1), autologous stem cell transplant (n =1), polatu-
zumab vedotin (n =1), and pomalidomide (n =1). The ORR for the 8
efficacy evaluable pts was 75% with 6 PR, 1 SD, and 1 NE. These pts
have been on treatment for 1.6, 2.3, 2.9+, 2.9+, 3.2+, 3.7, 6.4+, and
7.1+months (+indicates ongoing). The remaining pt continues on
treatment and is awaiting initial response assessment. No new safety
signals were identified in RT pts. Since data cut, 8 additional prior
treated pts with RT have been enrolled. Updated data with additional
followup in all 17 RT pts will be presented.
Conclusion: Pirtobrutinib showed promising initial efficacy in pts with
pretreated RT with extremely poor prognosis, including in pts who had
received prior chemoimmunotherapy and covalent BTK inhibitors.
EA previously submitted to EHA 2021.
The research was funded by: Loxo Oncology at Lilly
Keywords: Aggressive Bcell nonHodgkin lymphoma, Chronic
Lymphocytic Leukemia (CLL), Molecular Targeted Therapies
Conflicts of interests pertinent to the abstract
W. Jurczak
Research funding: Loxo Oncology, Janssen, AstraZeneca, Beigene
N. N. Shah
Other remuneration: Loxo Oncology
N. Lamanna
Research funding: Loxo Oncology
T. A. Eyre
Other remuneration: Loxo Oncology
J. Woyach
Other remuneration: Loxo Oncology
D. Wang
Employment or leadership position: Loxo Oncology at Lilly
Stock ownership: Loxo Oncology at Lilly
M. Yin
Employment or leadership position: Loxo Oncology at Lilly
Stock ownership: Loxo Oncology at Lilly
M. Balbas
Employment or leadership position: Loxo Oncology at Lilly
Stock ownership: Loxo Oncology at Lilly
B. C. Nair
Employment or leadership position: Loxo Oncology at Lilly
Stock ownership: Loxo Oncology at Lilly
SUPPLEMENT ABSTRACTS
-
191
E. Y. Zhu
Employment or leadership position: Loxo Oncology at Lilly
Stock ownership: Loxo Oncology at Lilly
D. E. Tsai
Employment or leadership position: Loxo Oncology at Lilly
Stock ownership: Loxo Oncology at Lilly
N. C. Ku
Employment or leadership position: Loxo Oncology at Lilly
Stock ownership: Loxo Oncology at Lilly
C. C. Coombs
Honoraria: Loxo Oncology
Research funding: Loxo Oncology
Other remuneration: Loxo Oncology
A. R. Mato
Consultant or advisory role: TG Therapeutics, Verastem
Research funding: Loxo Oncology, Genentech, Abbvie, AstraZeneca,
Adaptive, Pharmacyclics, Curio Sciences, Sunesis, Regeneron, Pfizer,
Aprea, Aptose, Verastem, and DTRM
Other remuneration: Loxo Oncology, Genentech, Abbvie, AstraZe-
neca, Adaptive, Pharmacyclics, and Curio Sciences
130 |PRELIMINARY RESULTS OF THE PHASE 2 STUDY OF
ZANUBRUTINIB IN PATIENTS WITH PREVIOUSLY TREATED B
CELL MALIGNANCIES INTOLERANT TO IBRUTINIB AND/OR
ACALABRUTINIB
M. Shadman
1
, J. P. Sharman
2
, M. Y. Levy
3
, R. Porter
4
, S. F. Zafar
5
, J. M.
Burke
6
, A. Chaudhry
7
, B. Freeman
8
, J. Misleh
9
, H. A. Yimer
10
, J. L.
Cultrera
11
, T. H. Guthrie
12
, E. Kingsley
13
, S. S. Rao
14
, D. Y. Chen
15
, X.
Zhang
15
, A. Idoine
15
, A. Cohen
15
, S. Feng
15
, J. Huang
15
, I. Flinn
16
1
Fred Hutchinson Cancer Research Center, University of Washington,
Clinical Research Division, Seattle, Washington, USA,
2
Willamette Valley
Cancer Institute and Research Center, Clinical Research Division, Eugene,
USA,
3
Texas OncologyBaylor Charles A. Sammons Cancer Center, Hema-
tology, Dallas, USA,
4
SSM Health Dean Medical Group, Hematology, Mad-
ison, USA,
5
Florida Cancer Specialists & Research Institute, Oncology, Fort
Myers, USA,
6
Rocky Mountain Cancer Centers, Oncology, Aurora, Colorado,
USA,
7
Summit Cancer Centers, Oncology, Spokane, USA,
8
Summit Medical
Group, Oncology, Florham Park, USA,
9
Medical Oncology Hematology
Consultants PA, Hematology, Newark, USA,
10
Texas OncologyTyler,
Oncology, Tyler, USA,
11
Florida Cancer Specialists & Research Institute,
Oncology, Leesburg, USA,
12
GenesisCare, Oncology, Jacksonville, USA,
13
Comprehensive Cancer Centers of Nevada, Oncology, Las Vegas, USA,
14
Alpha Med Physicians Group, Oncology & Hematology, Tinley Park, USA,
15
BeiGene (Beijing) Co., Ltd., Beijing, China and BeiGene USA, Inc., Hema-
tology, San Mateo, USA,
16
Sarah Cannon Research Institute/Tennessee
Oncology, Oncology, Nashville, USA
Introduction: Many patients (pts) with Bcell malignancies require
continuous treatment with Bruton tyrosine kinase inhibitors (BTKi).
Adverse events (AEs) are a common reason for ibrutinib (ibr) or
acalabrutinib (acala) discontinuation. Early data from BGB3111215
showed zanubrutinib (zanu) was well tolerated in pts with Bcell
malignancies who were intolerant to either ibr or acala. Here we
report preliminary results of the BGB3111215 trial, with a median
followup of 4.2 months.
Methods: Pts meeting protocol criteria for intolerance to ibr, acala, or
both (without documented progressive disease) were given
zanu monotherapy (160 mg twice daily or 320 mg once daily). Recur-
rence of AEs that led to intolerance of prior BTKi and additional safety
measures were assessed based on the Common Terminology Criteria
for AEs v5.0. Investigators determined responses using disease status
at study entry as baseline and established disease criteria.
Results: As of November 1, 2020 (cutoff), 44 pts (n =34 chronic
lymphocytic leukemia/small lymphocytic lymphoma, n =6 Walden-
ström macroglobulinemia, n =2 mantle cell lymphoma, n =2 marginal
zone lymphoma) were enrolled, received 1 dose of zanu, and analyzed
for safety. The median age was 70.5 y (range, 4991); median duration
of treatment was 4.2 months (range, 0.112.6). The median number of
prior regimens was 2 (range, 112). Regarding prior BTKi, 39 pts
received ibr only, 4 received ibr and acala, and 1 received acala only.
The median number of ibror acalaintolerant AEs per pt was 2 (range,
15). 83% of ibrand 78% of acalaintolerant events did not recur on
zanu; Table. At cutoff, 43 pts remained on treatment; 1 withdrew
consent due to zanuunrelated grade 3 syncope. Overall, 34 pts
(77.3%) reported any AE; most commonly reported AEs were myalgia
(n =9; 20.5%), contusion (n =8; 18.2%), dizziness (n =7; 15.9%), fatigue
(n =7; 15.9%), and cough (n =5; 11.4%). Grade 3 AEs were reported in
6 pts (13.6%), serious AEs in 1 pt (2.3%, febrile neutropenia and sal-
monella infection), AEs requiring dose interruptions in 6 pts (13.6%),
and AEs leading to dose reduction in 2 pts (4.5%). No AEs led to zanu
discontinuation. No deaths were reported. All efficacy evaluable pts
(26/26 [100%]) maintained (10 [38.5%]) or achieved deepening (16
[61.5%]) of their response.
Conclusions: Zanu provided an additional treatment option after
intolerance to other BTKi, demonstrating tolerability and sustained
or improved efficacy. Updated results will be presented.
EA previously submitted to ASCO and EHA 2021.
The research was funded by: BeiGene (Beijing) Co., Ltd., Beijing,
China and BeiGene USA, Inc., San Mateo, CA, USA
Keywords: Chronic Lymphocytic Leukemia (CLL)
Conflicts of interests pertinent to the abstract
M. Shadman
Consultant or advisory role: AbbVie, Genentech, AstraZeneca,
SoundBiologics, Pharmacyclics, Verastem, ADC Therapeutics, Bei-
Gene, Cellectar, Bristol Myers Squibb, Morphosys, TG Therapeutics,
InnatePharma, Kite Pharma, Adaptive Biotechnologies, Epizyme, and
AtaraBiotherapeutics
Research funding: Mustang Bio, Celgene, Bristol Myers Squibb,
Pharmacyclics, Gilead, Genentech, AbbVie, TG Therapeutics, Bei-
Gene, AstraZeneca, Sunesis
192
-
SUPPLEMENT ABSTRACTS
J. P. Sharman
Employment or leadership position: US Oncology Network
Consultant or advisory role: Pharmacyclics, Celgene, TG Therapeu-
tics, Genentech, AbbVie, Acerta Pharma/AstraZeneca, BeiGene,
Pfizer, Bristol Myers Squibb
Stock ownership: VelosBio
Research funding: Pharmacyclics, Genentech, Celgene, Acerta
Pharma, Gilead Sciences, Seattle Genetics, TG Therapeutics, Merck,
Takeda
M. Y. Levy
Employment or leadership position: Baylor University Med Center
Consultant or advisory role: BeiGene
Research funding: BeiGene
Other remuneration: Speakers' Bureau: BeiGene, AbbVie, Amgen,
AstraZeneca, BeiGene, Bristol Meyers Squibb, Dova, Epizyme, Gilead,
GSK, Janssen, Jazz, Karyopharm, Morphosys, Sanofi, Seattle Ge-
netics, Takeda
S. F. Zafar
Employment or leadership position: Florida Cancer Specialists +
Research Institute
Honoraria: Karyopharm, AstraZeneca, Bristol Meyers Squibb
Research funding: Sarah Canon Research Institute
Educational grants: AstraZeneca, Bristol Meyers Squibb
J. M. Burke
Consultant or advisory role: Genentech/Roche, AbbVie, Seattle Ge-
netics, Bayer, AstraZeneca, Adaptive Biotechnologies, Verastem,
MorphoSys, Kura Oncology, Epizyme, BeiGene, Kymera, Novartis
Other remuneration: Speakers' Bureau: Seattle Genetics, BeiGene
A. Chaudhry
Consultant or advisory role: Bayer
Stock ownership: Novartis
Honoraria: Bayer
H. A. Yimer
Employment or leadership position: Texas Oncology
Consultant or advisory role: AstraZeneca, Amgen, Karyopharm
Stock ownership: Epizyme, Karyopharm
Research funding: Janssen, BeiGene
Educational grants: Janssen, AstraZeneca, BeiGene, Karyopharm,
Amgen
Other remuneration: Speakers' Bureau: Janssen, AstraZeneca, Bei-
Gene, Karyopharm, Amgen, Takeda
J. L. Cultrera
Employment or leadership position: Florida Cancer Specialists and
Research Institute
Research funding: BeiGene, Takada, Genentech, Merck, Acerta, Eli
Lilly, AstraZeneca, Bristol Meyers Squibb, EMD Serono, Seattle
Genetics
Other remuneration: Speakers' Bureau: Celgene, Amgen, Aurobindo
Pharma
T. H. Guthrie
Employment or leadership position: Genesis Care LTD
D. Y. Chen
Employment or leadership position: BeiGene
Stock ownership: BeiGene
X. Zhang
Employment or leadership position: BeiGene
Stock ownership: BeiGene
A. Idoine
Employment or leadership position: BeiGene
Stock ownership: BeiGene
A. Cohen
Employment or leadership position: BeiGene
Stock ownership: BeiGene
S. Feng
Employment or leadership position: BeiGene
Stock ownership: BeiGene, Amgen, Nektar, Illumina, Annexon,
Hutchison China MediTech
Other remuneration: Patents, Royalties, OtherIntellectual Property:
BeiGene USA Inc.
J. Huang
Employment or leadership position: BeiGene
Consultant or advisory role: BeiGene
Stock ownership: BeiGene
Educational grants: BeiGene
I. Flinn
Consultant or advisory role: AbbVie, AstraZeneca, BeiGene, Gilead
Sciences, Great Point Partners, Iksuda Therapeutics, Janssen, Juno
Therapeutics, Kite Pharma, MorphoSys, Nurix Therapeutics, Phar-
macyclics, Roche, Seattle Genetics, Takeda, Unum Therapeutics,
Verastem, Yingli Pharmaceuticals
Recurrence and Severity Chage of AEs Leading of lbr or Acala Intolearnce
SUPPLEMENT ABSTRACTS
-
193
Research funding: AbbVie, Acerta Pharma, Agios, ArQule, AstraZe-
neca, BeiGene, Calithera Biosciences, Celgene, Constellation Phar-
maceuticals, Curis, Forma Therapeutics, Forty Seven, Genentech,
Gilead Sciences, IGM Biosciences, Incyte, Infinity Pharmaceuticals,
Janssen, Juno Therapeutics, Karyopharm Therapeutics, Kite Pharma,
Loxo, Merck, MorphoSys, Novartis, Pfizer, Pharmacyclics, Portola
Pharmaceuticals, Rhizen Pharmaceuticals, Roche, Seattle Genetics,
Takeda, Teva, TG Therapeutics, Trillium Therapeutics, Triphase
Research & Development Corp., Unum Therapeutics, Verastem
131 |UPDATED EFFICACY AND SAFETY RESULTS OF
ORELABRUTINIB IN THE TREATMENT OF RELAPSED OR
REFRACTORY CHRONIC LYMPHOCYTIC LEUKEMIA/SMALL CELL
LEUKEMIA
W. Xu
1
, Y. Song
2
, T. Wang
3
, S. Yang
4
, L. Liu
5
, Y. Hu
6
, W. Zhang
7
, J.
Zhou
8
, S. Gao
9
, K. Ding
10
, H. Zhang
11
, Z. Zhu
12
, S. Wang
13
, B. Xu
14
, J.
Hu
15
, T. Liu
16
, C. Ji
17
, Z. Xia
18
, Y. Li
19
, X. Wang
20
, R. Zhao
21
, B.
Zhang
22
, J. Li
1
1
Pukou CLL Center, The First Affiliated Hospital of Nanjing Medical
University, Jiangsu Province Hospital, Collaborative Innovation Center for
Cancer Personalized Medicine, Hematology Department, Nanjing, China,
2
Affiliated Cancer Hospital of Zhengzhou University, Hematology
Department, Zhengzhou, China,
3
National Clinical Research Center for
Blood Disease, State Key Laboratory of Experimental Hematology, Blood
Disease Hospital and Institute of Hematology, Chinese Academy of
Medical Sciences & Peking Union Medical College, Lymphoma Center,
Tianjin, China,
4
Peking University People's Hospital, Hematology
Department, Beijing, China,
5
The Fourth Hospital of Hebei Medical
University, Hematology Department, Shijiazhuang, China,
6
Union
Hospital, Tongji Medical College, Huazhong University of Science and
Technology, Hematology Department, Wuhan, China,
7
Peking Union
Medical College Hospital, Hematology Department, Beijing, China,
8
Tongji
Hospital Huazhong University of Science and Technology, Hematology
Department, Wuhan, China,
9
The First Hospital, Jilin University,
Hematology Department, Jilin, China,
10
The First Affiliated Hospital of
University of Science and Technology of China, Hematology Department,
Hefei, China,
11
Tianjin Medical University Cancer Institute & Hospital,
Lymphoma, Tianjin, China,
12
Henan Provincial People's Hospital,
Hematology Department, Zhengzhou, China,
13
Guangzhou First People's
Hospital, Hematology Department, Guangzhou, China,
14
The First
Affiliated Hospital of Xiamen University, Hematology Department,
Xiamen, China,
15
Fujian Medical University Union Hospital, Fujian
Institute of Hematology, Fujian Provincial Key Laboratory on Hematology,
Hematology Department, Fuzhou, China,
16
West China Hospital Sichuan
University, Hematology Department, Chengdu, China,
17
Qilu Hospital,
Cheeloo College of Medicine, Shandong University, Hematology
Department, Jinan, China,
18
Sate Key Laboratory of Oncology in South
China, Collaborative Innovation of Cancer Medicine, Sun Yatsen Uni-
versity Cancer center, Department of Hematologic Oncology, Guangzhou,
China,
19
The First Affiliated Hospital of China Medical University, He-
matology Department, Shenyang, China,
20
School of Medicine, Shandong
University, Hematology, Jinan, China,
21
Beijing InnoCare Pharma Tech
Co., Ltd, Beijing, China,
22
Beijing InnoCare Pharma Tech Co., Ltd, Beijing,
China
Introduction: Orelabrutinib is a novel and highly selective irrevers-
ible BTK inhibitor. We previously reported that orelabrutinib had
high bioavailability with 100% BTK occupancy at 24 hours at 150
mg daily dosing regimen and had demonstrated excellent safety and
efficacy profiles in a phase II trial of r/r CLL/SLL. Here we present an
updated result following the extended time of treatment.
Method: This is an openlabel, multicenter, phase II study to evaluate
the safety and efficacy following an oral daily administration of
orelabrutinib. Responses were assessed per 2008 IWCLL criteria.
Results: A total of 80 patients with r/r CLL/SLL were enrolled.
Eligible patients received 1 prior treatment with median age of 60.0
years. There are 70% of patients for Rai stage 34 disease, 22.5% for
del(17p) and/or TP53 mutation, 41.3% for unmutated IGHV and
23.8% for del(11q). The median followup time was 25.6 months, with
71.3% remaining on study treatment.
The efficacy results were evaluated by both IRC and in-
vestigators, with the ORR of 92.5 % with 16.3% CR/CRi, 65.0% PR
and 11.3% PRL by IRC, and the ORR of 93.8% with 21.3% CR/CRi,
61.3% PR, and 11.3% PRL by investigators. These results revealed
high concordance rate for overall response assessments between
IRC and investigator. Median time for achieving first response was
1.87 months. The median DOR and PFS were not reached. The
estimated 18month DOR was 77.2%, and PFS was 78.7% by IRC.
The ORR was 100% in patients with Del(17p) and/or TP53 mutation.
The ORR was 94.7% for Del(11q)) and 93.9% for unmutated IGHV.
Comparing to the previous CR/CRi rate of 8.8% and 10.0% reported
at median follow up of 14.3 months, the updated CR/CRi rate had
achieved 21.3% and 16.3% by investigator and IRC assessment,
respectively. Orelabrutinib showed a significant higher CR/CRi rate
in r/r CLL/SLL comparing to other BTK inhibitors at a similar median
followup period.
Extended followup analysis did not reveal new safety nor
toxicity concerns. Similar to the previous reported safety results,
most AEs were mild to moderate. The most frequent AEs were he-
matological toxicities, upper respiratory tract infection, pneumonia
and hypokalemia. No case of atrial fibrillation nor secondary malig-
nancy was reported, no patient was observed for 3 grade hyper-
tension and only one patient had 3 grade diarrhea. Major
hemorrhage was reported in 2 patients, one with intracranial hem-
orrhage (65year old patient with >10 years hypertension) and the
other with vitreous hemorrhage which was assessed as unlikely
related to the treatment of orelabrutinib.
Conclusion: This updated study result further confirms that orelab-
rutinib is efficacious in treating r/r CLL patients with a significant
higher CR rate, durable response and improved safety profiles. Ore-
labrutinib provides a favorable therapeutic choice for patients with r/r
CLL/SLL and a potential best candidate for the combination therapy.
EA previously submitted to regional or national meetings (up to
1000 attendees)
194
-
SUPPLEMENT ABSTRACTS
The research was funded by: Beijing InnoCare Pharma Tech Co., Ltd
Keywords: Chronic Lymphocytic Leukemia (CLL)
Conflicts of interests pertinent to the abstract
R. Zhao
Employment or leadership position: Employment
B. Zhang
Employment or leadership position: Employment
132 |SAFETY AND EFFECTIVENESS OF VENETOCLAX
MONOTHERAPY IN ELDERLY PATIENTS WITH RELAPSED/
REFRACTORY CLL UNDER REALLIFE CONDITIONS DATA
FROM THE OBSERVATIONAL STUDY VERVE
I. Schwaner
1
, H. Hebart
2
, C. Losem
3
, T. Wolff
4
, J. Huelsenbeck
5
, B.
Schmidt
6
, D. Rossi
7
, T. Noesslinger
8
1
Onkologie Kurfürstendamm, Berlin, Germany , Hematology/Oncology,
Berlin, Germany,
2
Kliniken Ostalb, Hematology/Oncology, Mutlangen,
Germany,
3
MVZ Onkologie und Hämatologie , Hematology/Oncology,
Neuss, Germany,
4
Onkologie Lerchenfeld, Hematology/Oncology,
Hamburg, Germany,
5
AbbVie Deutschland GmbH & Co. KG, Hematology/
Oncology, Wiesbaden, Germany,
6
HämatologischOnkologische
Gemeinschaftspraxis, Hematology/Oncology, Munich, Germany,
7
Institute
of Oncology Research, Hematology/Oncology, Bellinzona, Switzerland,
8
3.
Medizinische Abteilung für Hämatologie und Onkologie, Hanusch
Krankenhaus, Hematology/Oncology, Vienna, Austria
Background: In clinical trials, treatment of chronic lymphocytic
leukaemia (CLL) with venetoclax (Ven) has shown promising efficacy
and good tolerability. However, patients treated in clinical trial
often represent a selected group not representative for patients
treated in daily practice. Prospective realworld data on Ven usage
are limited.
Aim: We conduct a prospective noninterventional observational
study assessing effectiveness, safety, and quality of life in relapsed/
refractory patients (RR) treated with Ven in Austria, Germany, and
Switzerland. The population enrolled is representative for patients
treated with Ven according to local label. This report focuses on
patients treated with Ven monotherapy.
Methods: Adult patients with CLL requiring therapy treated with Ven
according to local label are eligible for the study. Patients’ visits are
scheduled at the physician's discretion and according to clinical
practice. Study documentation is possible at baseline, weekly during
rampup, monthly until the end of 6 months and 3monthly after-
wards up to a maximum of 3 years. Response assessment according
to IwCLL criteria can be documented at the end of rampup, after 3,
12, and 24 months.
Results: Until November 15th, 2020, 62 patients were enrolled, 57
had received at least one dose of Ven (=safety population), and for
43 treatment response had been documented at least once (=effec-
tiveness population). Median age was 75 years, 64% of patients were
male, 69% had at least one comorbidity, most commonly cardiovas-
cular (45%), 61% received comedication. Patients were pretreated
with a median of 2 (range 110) lines of therapy, i.e., chemo
immunotherapy (69%) and therapy with Bcell receptor inhibitors
(81%). Del(17p), TP53 mutation, and presence of unmutated IGHV
had been diagnosed in 37%, 35%, and 29%, respectively (excl. missing
data: 43%, 45%, 70%).
With a median observation time of 210 (range 1879) days, 93% of
patients experienced at least one AE, 63% CTCAE grade 3/4 AEs, SAEs
40%. There were four grade 5 AEs reported. The most common AEs in
any grade were thrombocytopenia, diarrhoea, neutropenia (23%, 21%,
15%). The median for progressionfree survival (PFS) and overall sur-
vival (OS) has not been reached, the 12month estimates were 72%
(PFS) and 78,2% (OS). At 6 and 12 months, an estimated 67,6 and
60,0%, respectively, remain on therapy. The reported best overall
response at 12 months was 67,4% (CR+CRi 32,6%; PR: 34,8%).
Conclusion: Under realworld conditions, Ven monotherapy is used
in elderly R/R CLL patients. The treatment was well tolerated. Pa-
tients presented with highrisk features, e.g. del17p or BCRi pre-
treatment; yet, the response rate was high and the proportion of
patients with deep response increased over time. Our study confirms
findings from Venetoclax PhaseIIstudies in R/R CLL patients
treated under realworld conditions.
The research was funded by: AbbVie sponsored this study and
contributed to the design, study conduct, and analysis. AbbVie
participated in the interpretation of data, review, and approval of the
abstract. No honoraria or payments were made for authorship.
All authors had access to all relevant data.
Keywords: Chronic Lymphocytic Leukemia (CLL), Molecular Targeted
Therapies
Conflicts of interests pertinent to the abstract
I. Schwaner
Honoraria: Abbvie, Amgen, AstraZeneca, Celgene, Janssen, Novartis,
Roche, Servier
H. Hebart
Consultant or advisory role: AbbVie, AstraZeneca, Celgene, Janssen,
Roche
T. Wolff
Honoraria: Novartis, Celgene, Roche, Bayer, Teva, AbbVie
Research funding: Novartis, Celgene, Roche, Bayer, Teva, AbbVie
J. Huelsenbeck
Employment or leadership position: AbbVie
Stock ownership: AbbVie
B. Schmidt
Consultant or advisory role: AbbVie, Incyte, Novartis, SanofiAventis,
Alexion, Biotest, Takeda, Janssen
D. Rossi
Honoraria: Abbvie, AstraZeneca, Gilead, Janssen, Verastem, Roche,
Cellestia
SUPPLEMENT ABSTRACTS
-
195
Research funding: Abbvie, AstraZeneca, Gilead, Janssen, Verastem,
Roche, Cellestia
T. Noesslinger
Consultant or advisory role: AbbVie, Celgene, Roche, Janssen,
AstraZeneca, Gilead
133 |IBRUTINIB TOLERABILITY AND OUTCOME IN PATIENTS
WITH HIGHRISK CHRONIC LYMPHOCYTIC LEUKEMIA
A. Condoluci
1
, L. TerzidiBergamo
2
, G. Forestieri
2
, R. Moia
3
, C.
Deambrogi
3
, M. Deodato
4
, A. M. Frustaci
4
, M. Merli
5
, R. Mattar-
ucchi
5
, F. Autore
6
, G. Fahrni
7
, L. Scarfò
8
, D. Gussetti
9
, P. Bulian
9
, A.
Zanatta
9
, V. Spina
2
, M. R. Faderl
1
, A. Bruscaggin
2
, K. Pini
2
, D. Pif-
faretti
2
, R. Koch
2
, M. C. Pirosa
1
, M. G. Cittone
1
, J. Passweg
10
, F.
Cavalli
11
, E. Zucca
12
, B. Gerber
1
, S. Gillessen
12
, G. Stüssi
1
, V. Gattei
9
,
P. Ghia
8
, M. Gregor
7
, L. Laurenti
6
, F. Passamonti
5
, A. Tedeschi
4
, G.
Gaidano
3
, D. Rossi
1
1
Oncology Institute of Southern Switzerland, Clinic of Hematology,
Bellinzona, Switzerland,
2
Institute of Oncology Research, Laboratory of
Experimental Hematology, Bellinzona, Switzerland,
3
University of Eastern
Piedmont, Department of Translational Medicine, , Division of
Hematology, Novara, Italy,
4
ASST Grande Ospedale Metropolitano
Niguarda, Niguarda Cancer Center, Department of Hematology, Milan,
Italy,
5
University of Insubria, Ospedale di Circolo e Fondazione Macchi,
Department of Hematology, Varese, Italy,
6
Fondazione Policlinico
Universitario A. Gemelli, Catholic University of the Sacred Hearth,
Hematology Institute, Rome, Italy,
7
Cantonal Hospital Lucerne, Division of
Haematology and Central Haematology Laboratory, Lucerne, Switzerland,
8
IRCCS San Raffaele Scientific Institute and VitaSalute San Raffaele
University, Strategic Research Program on CLL, Division of Experimental
Oncology, Milan, Italy,
9
Centro di Riferimento Oncologico di Aviano
(CRO), IRCCS, Clinical and Experimental OncoHematology Unit, Aviano,
Italy,
10
University Hospital Basel, Department of Haematology, Basel,
Switzerland,
11
Università della Svizzera Italiana, Institute of Oncology
Research, Bellinzona, Switzerland,
12
Oncology Institute of Southern
Switzerland, Clinic of Oncology, Bellinzona, Switzerland
Background: Overall, ten independent retrospective studies
addressed the question of the tolerability of ibrutinib in the real
world setting. Discontinuation rates ranged from 5% to 29%. Such
heterogeneity may reflect differences in the case mix, follow up and
accessibility to next treatments. Dose reduction/transient interrup-
tion rates ranged from 22% to 32%. The impact of intolerance on
ibrutinib effectiveness according to baseline CLL biology is largely
unknown. We assessed whether outcomes of patients with highrisk
CLL is affected by ibrutinib discontinuation, interruption, or dose
reduction due to intolerance.
Methods: The IOSIEMA001 and the IOSIEMA003 observational
prospective studies (NCT02827617; NCT03280394) enrolled pa-
tients with CLL treated with ibrutinib according to prescribing in-
dications in Switzerland and Italy. Pretreatment demographics,
disease data, mutation analysis by LyV4.0 CAPPseq assay, infor-
mation on treatment discontinuation, interruption and dose reduc-
tion, and efficacy outcomes were collected.
Results: In stotal, 90 patients were included in the per protocol
population. Baseline features include age >65 years in 71% of cases,
male gender in 61%, previous treatment in 47%, beta2
microglobulin >5 mg/L in 40%, lactate dehydrogenase >ULN in
55%, TP53 disruption in 83%, and unmutated IGHV in 78%. Baseline
mutations of SF3B1 (30%), NOTCH1 (28%), ATM (15%), EGR2 (13%),
196
-
SUPPLEMENT ABSTRACTS
MGA (11%), POT1 (11%), and BIRC3 (10%) were reported in 10% of
cases. The median followup of patients was 2.8 years. Median time
on ibrutinib was 29 months. Discontinuation of ibrutinib due to any
reason except progressive disease (PD) was reported in 21% of pa-
tients and their median time on ibrutinib was 17 months. Median
time to discontinuation due to any reason except PD was 16 months.
At least 1 interruption was reported in 31% of patients, and 6%
interrupted treatment >1 time. The median consecutive days of
interruption was 28 and the median total days of interruption was
38. Dose reduction was required by 25% of patients, including 5%
who reduced to 140 mg/d. Median dose intensity (proportion of
administered vs planned doses of ibrutinib 420 mg/d) was 93.4%.
Threeyears PFS of the per protocol cohort was 80.3% (CI 69.992.2).
Early discontinuation due to any reason except PD, treatment
interruption, regardless of duration (1, 8, 14 and 21 consecu-
tive days), and dose reduction had no impact on PFS. By recursive
partitioning, PFS stratification based on the best cutoff for dose
intensity did not show a negative outcome, indicating no com-
pounded effect of both dose reduction and interruption.
Conclusions: Ibrutinib treatment modifications seem not to have
major impact on PFS in patients with highrisk CLL. The impact of
ibrutinib dose intensity during the first months of therapy on PFS,
and the impact of ibrutinib tolerability on time to next treatment will
be explored in this dataset.
Keywords: Tumor Biology and Heterogeneity, Diagnostic and Prog-
nostic Biomarkers, Ongoing Trials
Conflicts of interests pertinent to the abstract
E. Zucca
Honoraria: AbbVie; AstraZeneca; Janssen
Research funding: AbbVie; AstraZeneca; Janssen
D. Rossi
Honoraria: AstraZeneca; AbbVie; Janssen
Research funding: AstraZeneca; AbbVie; Janssen
134 |EFFICACY AND DISCONTINUATION RATE OF IBRUTINIB
IN TREATMENT NAIVE CHRONIC LYMPHOCYTIC LEUKEMIA
PATIENTS WITH TP53 ABNORMALITIES. A REALLIFE CAMPUS
CLL STUDY
A. Visentin
1
, F. R. Mauro
2
, F. Cibien
3
, C. Vitale
4
, G. Reda
5
, A. Fresa
6
, S.
Ciolli
7
, D. Pietrasanta
8
, M. Marchetti
8
, R. Murru
9
, M. Gentile
10
, G. M.
Rigolin
11
, F. M. Quaglia
12
, L. Scarfò
13
, P. Sportoletti
14
, S. Pravato
1
, L.
Romano Gargarella
1
, M. Facco
1
, F. Piazza
1
, M. Marchetti
8
, M. Coscia
4
,
L. Laurenti
6
, S. Molica
15
, G. Pizzolo
12
, R. Foà
2
, A. Cuneo
11
, L. Trentim
1
1
Hematology and Clinical Immunology Unit, Department of Medicine,
University of Padova, Padova, Italy,
2
Hematology Unit, Department of
Translational and Precision Medicine, "Sapienza" University, Rome, Italy,
3
Hematology Unit, Ca’ Foncello Hospital, Treviso, Italy,
4
Department of
Molecular Biotechnology and Health Sciences, , University of Torino and
Division of Hematology, A.O.U. Città della Salute e della Scienza di Torino,
Torino, Italy,
5
Hematology Unit, Fondazione IRCCS Ca' Granda Ospedale
Maggiore, Milan, Italy,
6
Hematology Institute, Fondazione Policlinico
Universitario Agostino Gemelli IRCSS, Roma, Italy,
7
Hematology Unit,
Careggi Hospital, University of Florence, Florence, Italy,
8
Division of
Hematology, A.O. SS Antonio e Biagio and Cesare Arrigo, Alessandria,
Italy,
9
Hematology and Stem Cell Transplantation Unit, Ospedale A.
Businco, ARNAS “G. Brotzu”, Cagliari, Italy,
10
Hematology unit,
Department of HematoOncology, Annunziata Hospital, Cosenza, Italy,
11
Hematology section, Department of Medical Sciences, Azienda
OspedalieraUniversitaria, Arcispedale S. Anna, University of Ferrara,
Ferrara, Italy,
12
Department of Medicine, Section of Hematology, Uni-
versity of Verona & Azienda Ospedaliera Universitaria Integrata, Verona,
Italy,
13
Strategic program on CLL, University health and Science “San
Raffaele”, Milan, Italy,
14
Hematology and Clinical Immunology unit, Uni-
versity of Perugia, Perugia, Italy,
15
Department HematologyOncology,
Azienda Ospedaliera PuglieseCiaccio, Catanzaro, Italy
Backgroung: Disruption of the TP53 gene, including 17p13 deletion
(17p) and/or TP53 mutation (TP53m), is a negative prognostic
biomarker in chronic lymphocytic leukemia (CLL). Ibrutinib has
proven to be highly active in CLL with unfavorable features, but data
on treatmentnaive (TN) patients with TP53 abnormalities (abn)
derive from almost 90 patients included in 5 clinical trials.
The aim of this study is to describe the efficacy and discontinu-
ation rate of ibrutinib in TN CLL patients with TP53 abn in the real
life setting.
Methods: Medical charts of CLL patients followed in 14 centers
belonging to the Italian Campus CLL network were retrospectively
reviewed to identify CLL with 17p(cutoff 10%) and/or TP53m
treated frontline with ibrutinib. The primary endpoint was the rate
of discontinuation. Secondary endpoints were progressionfree sur-
vival (PFS), timetonext treatment (TTNT), overall survival (OS).
Response assessment was done according to the iwCLL 2018
guidelines.
Results: One hundred TN CLL patients were recruited in this study.
Fiftyone patients were male, the median age at the start of ibrutinib
was 71 years (range 3787), including 35 octogenarians, the median
CIRS was 4 (range 013), 42 had a creatinine clearance <60ml/min.
Seventyseven patients were IGHV unmutated, 33 displayed only
17p, 22 only TP53m and 45 both 17pand TP53m.
The overall response rate was 84%, including 10% of complete
remissions. After a median followup of 24 months, 13 patients
relapsed, 10 required further therapy, 2 developed a Richter syn-
drome (RS) and 8 died (4 infections, 1 melanoma, 1 RS, 1 sudden
death). The median PFS, TTNT and OS have not been not reached.
The 12, 24 and 36month PFS was 91%, 82% and 75%, respectively.
The 12, 24 and 36month TTNT was 94%, 89% and 82%. The 12, 24
and 36month OS was 96%, 92% and 87% (Figure 1A). PFS was
shorter in patients 75 years (2yy PFS 69% vs 89%, p =0.04), who
did not respond (85% vs 66%, p =0.03) but was not influenced by
IGHV status.
Twentyeight patients discontinued treatment, 20 for adverse
events (AE) (8 infections, 5 atrial fibrillations, 4 others and 3 deaths),
SUPPLEMENT ABSTRACTS
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